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US20170202818A1 - Methods and compositions to modify gsk-3 activity - Google Patents

Methods and compositions to modify gsk-3 activity Download PDF

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US20170202818A1
US20170202818A1 US15/326,782 US201515326782A US2017202818A1 US 20170202818 A1 US20170202818 A1 US 20170202818A1 US 201515326782 A US201515326782 A US 201515326782A US 2017202818 A1 US2017202818 A1 US 2017202818A1
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gsk
substituted
cob
chosen
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Douglas Goetz
Kelly D. McCall
Stephen C. Bergmeier
Frank L. Schwartz
Pooja Bhatt
Sudhir Deosarkar
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Ohio University
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    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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Definitions

  • the present disclosure relates generally to modulation of glycogen synthase kinase-3 [i.e., GSK-3( ⁇ and/or ⁇ )] activity, modulation of GSK-3 signaling, and treatment of GSK-3 mediated disorders. More particularly, the present disclosure relates to one or more methods for modulating GSK-3 activity, modulating GSK-3 signaling, and treating GSK-3 mediated disorders using novel imidazole and/or thiazole compounds.
  • the protein kinases of which there are over 500 in the human genome, are germane to cellular signal transduction and consequently to a plethora of cellular processes.
  • the kinases bind to protein substrates and high energy donors (e.g. ATP) and transfer a phosphate group to the substrate.
  • high energy donors e.g. ATP
  • glycogen synthase kinase-3 [i.e., GSK-3( ⁇ and/or ⁇ )] has been implicated in a host of pathologies including malaria, cancer, insulin resistance, type 2 diabetes mellitus, muscle wasting (i.e., muscle atrophy), neurodegenerative diseases, cardiovascular diseases, myocardial diseases, pathological inflammation, renal diseases, HIV-related neurological disorders, sepsis, toxic shock, psychiatric diseases, and central nervous system (i.e., CNS) diseases.
  • GSK-3( ⁇ and/or ⁇ ) glycogen synthase kinase-3
  • GSK-3 is expressed as two isozymes, GSK-3 ⁇ and GSK-3 ⁇ . Though it is clear that the roles of these isozymes in pathology and physiology are not identical, the understanding of the differences in their function is in the early stages and the importance of developing ⁇ -specific or ⁇ -specific inhibitors is unclear. To date, most inhibitors do not discriminate between these two isoforms.
  • Lithium a cation widely used to treat bipolar and other severe mental disorders, is a relatively weak GSK-3 inhibitor. The reported mechanism is via competition with Mg 2+ ions and enhancing serine phosphorylation. Other metals have also been shown to be inhibitors of GSK-3 including bivalent zinc ions.
  • ATP-competitors Numerous ATP-competitors have been identified. These were obtained through modification of compounds that exist naturally (e.g., indirubins) or through organic synthesis (e.g., AR-R014418 and AZD-1080). Many of these agents are quite potent, having IC 50 values in the nanomolar range. All of these compounds demonstrated biological activity and one, AZD-1080, did enter clinical trials but was withdrawn. The fact that all protein kinases have a binding pocket for a high energy donor that is typically ATP, raises the possibility that ATP-competitive inhibitors may have limited specificity. Some of the GSK-3 ATP-competitive inhibitors did show specificity against a small panel of kinases.
  • non-ATP competitive GSK-3 inhibitors Although fewer non-ATP competitive GSK-3 inhibitors have been identified, several have been developed including those obtained from natural sources (e.g., manzamines) or organic synthesis. In addition, a peptide (e.g., L803-mts) has been developed that is a non-ATP competitive inhibitor. In general, these inhibitors tend to be less potent than the ATP-competitive inhibitors having IC 50 values in the low micromolar range, compared to the nanomolar range often seen for ATP-competitive inhibitors.
  • One set of inhibitors, generated through organic synthesis, are the Thiadiazolidindiones (i.e., TDZD).
  • tideglusib i.e., NP-12
  • TAUROS the TAUROS study for the treatment of progressive supranuclear palsy
  • the primary endpoint was not achieved.
  • a positive clinical effect was observed in an analysis of a sub-set of patients in the group. Specifically, those treated with tideglusib had reduced progression of global cerebral atrophy compared to placebo.
  • modulators such as, e.g., inhibitors, of GSK-3 activity and methods for modulating, such as, e.g., inhibiting, GSK-3 activity, modulating GSK-3 signaling, and treating GSK-3 mediated disorders.
  • the present disclosure is based on the discovery that imidazole and/or thiazole compounds can be used to modulate GSK-3 activity, to modulate GSK-3 signaling, and/or to treat GSK-3 mediated disorders. Accordingly, provided herein is an entirely new paradigm for disease intervention.
  • methods for modulating glycogen synthase kinase-3 (i.e., GSK-3) activity in a cell expressing GSK-3 are provided. Such methods include contacting the cell with a therapeutically effective amount of at least one compound of General Formula (I) or (II):
  • R 1 is chosen from C 1 to C 10 aliphatic or heteroaliphatic groups, optionally substituted with one or more aryl groups, substituted aryl groups, heteroaryl groups, substituted heteroaryl groups, or combination thereof;
  • R 2 is chosen from aryl groups, substituted aryl groups, heteroaryl groups, substituted heteroaryl groups, and coumarin;
  • R 3 is chosen from —H, C 1 to C 10 aliphatic or heteroaliphatic groups, phenyl, or substituted phenyl, wherein the aliphatic or heteroaliphatic groups are optionally substituted with one or more phenyl groups, aryl groups, heteroaryl groups, substituted heteroaryl groups, or combination thereof;
  • X is S or O; and
  • Y is S or NH; with the proviso that when R 2 is phenyl and R 3 is —H, at least one of the following is true: (a) R 1 is a C 1 to C
  • kits for modulating GSK-3 signaling include contacting a cell expressing GSK-3 with a therapeutically effective amount of at least one compound of General Formula (I) or (II):
  • R 1 is chosen from C 1 to C 10 aliphatic or heteroaliphatic groups, optionally substituted with one or more aryl groups, substituted aryl groups, heteroaryl groups, substituted heteroaryl groups, or combination thereof;
  • R 2 is chosen from aryl groups, substituted aryl groups, heteroaryl groups, substituted heteroaryl groups, and coumarin;
  • R 3 is chosen from —H, C 1 to C 10 aliphatic or heteroaliphatic groups, phenyl, or substituted phenyl, wherein the aliphatic or heteroaliphatic groups are optionally substituted with one or more phenyl groups, aryl groups, heteroaryl groups, substituted heteroaryl groups, or combination thereof;
  • X is S or O; and
  • Y is S or NH; with the proviso that when R 2 is phenyl and R 3 is —H, at least one of the following is true: (a) R 1 is a C 1 to C
  • kits for treating GSK-3-mediated disorders include administering to the subject a therapeutically effective amount of at least one compound of General Formula (I) or (II):
  • R 1 is chosen from C 1 to C 10 aliphatic or heteroaliphatic groups, optionally substituted with one or more aryl groups, substituted aryl groups, heteroaryl groups, substituted heteroaryl groups, or combination thereof;
  • R 2 is chosen from aryl groups, substituted aryl groups, heteroaryl groups, substituted heteroaryl groups, and coumarin;
  • R 3 is chosen from —H, C 1 to C 10 aliphatic or heteroaliphatic groups, phenyl, or substituted phenyl, wherein the aliphatic or heteroaliphatic groups are optionally substituted with one or more phenyl groups, aryl groups, heteroaryl groups, substituted heteroaryl groups, or combination thereof;
  • X is S or O; and
  • Y is S or NH; with the proviso that when R 2 is phenyl and R 3 is —H, at least one of the following is true: (a) R 1 is a C 1 to C
  • FIG. 1A is a graph of COB-152 (i.e., I-152) concentration (nM) with respect to percent inhibition of GSK-3 ⁇ activity;
  • FIG. 1B is a graph of COB-152 (i.e., I-152) concentration (nM) with respect to percent inhibition of GSK-3 ⁇ activity;
  • FIG. 2A is a graph of COB-187 (i.e., I-187) concentration (nM) with respect to percent inhibition of GSK-3 ⁇ activity;
  • FIG. 2B is a graph of COB-187 (i.e., I-187) concentration (nM) with respect to percent inhibition of GSK-3 ⁇ activity;
  • FIG. 3 is a graph of cyclin-dependent kinases CDK1, CDK2, CDK/p25, CDK5/p35, CDK7, CDK8, CDK9 Cyclin K, CDK9 Cyclin Ti, GSK-3 ⁇ (i.e., GSK3 alpha) and GSK-3 ⁇ (GSK3 beta) activity with respect to percent inhibition by COB-152 (i.e., I-152) and/or COB-187 (i.e., 1-187);
  • COB-152 i.e., I-152
  • COB-187 i.e., 1-187
  • FIG. 4B is a western blot of ⁇ -catenin, GSK-3 ⁇ , GSK-3 ⁇ , and ⁇ -actin (serving as a control) expression in RAW 264.7 murine macrophages treated with DMSO (0.1% v/v) or COB-187 (0.5 ⁇ M, 1 ⁇ M, 5 ⁇ M, 10 ⁇ M, or 25 ⁇ M) for 5 hours;
  • FIG. 5A is a western blot of ⁇ -catenin, GSK-3 ⁇ , GSK-3 ⁇ , and ⁇ -actin (serving as a control) expression in PMA differentiated THP-1 cells treated with DMSO (0.1% v/v) or COB-152 (0.5 ⁇ M, 1 ⁇ M, 5 ⁇ M, 10 ⁇ M, or 25 ⁇ M) for 5 hours;
  • FIG. 5B is a western blot of ⁇ -catenin, GSK-3 ⁇ , GSK-3 ⁇ , and ⁇ -actin (serving as a control) expression in PMA differentiated THP-1 cells treated with DMSO (0.1% v/v) or COB-187 (0.5 ⁇ M, 1 ⁇ M, 5 ⁇ M, 10 ⁇ M, or 25 ⁇ M) for 5 hours;
  • FIG. 6B is a graph of untreated RAW 264.7 murine macrophages, RAW 264.7 murine macrophages treated with DMSO (0.1% v/v), and RAW 264.7 murine macrophages treated with COB-187 (4 ⁇ M, 20 ⁇ M, or 40 ⁇ M) for 5 hours with respect to fold change in ⁇ -catenin mRNA expression;
  • FIG. 8A is a graph of untreated human macrophages (i.e., Untrx) and human macrophages treated with A ⁇ (1-42) peptides (i.e., Abeta, 1 check for missing ⁇ M, 5 ⁇ M, 10 ⁇ M, 25 ⁇ M, or 50 ⁇ M) for 5 and 24 hours with respect to fold change in IL-6 mRNA expression;
  • Untrx untreated human macrophages
  • a ⁇ (1-42) peptides i.e., Abeta, 1 check for missing ⁇ M, 5 ⁇ M, 10 ⁇ M, 25 ⁇ M, or 50 ⁇ M
  • FIG. 8B is a graph of untreated human macrophages (i.e., Untrx) and human macrophages treated with A ⁇ (1-42) peptides (i.e., Abeta, 1 ⁇ M, 5 ⁇ M, 10 ⁇ M, 25 ⁇ M, or 50 M) for 5 and 24 hours with respect to fold change in TNF- ⁇ mRNA expression;
  • Untrx untreated human macrophages
  • a ⁇ (1-42) peptides i.e., Abeta, 1 ⁇ M, 5 ⁇ M, 10 ⁇ M, 25 ⁇ M, or 50 M
  • FIG. 8D is a graph of untreated human macrophages (i.e., Untrx) and human macrophages treated with A ⁇ (1-42) peptides (i.e., Abeta, 1 ⁇ M, 5 ⁇ M, 10 ⁇ M, 25 ⁇ M, or 50 M) for 5 and 24 hours with respect to fold change in IL-1 ⁇ mRNA expression;
  • Untrx untreated human macrophages
  • a ⁇ (1-42) peptides i.e., Abeta, 1 ⁇ M, 5 ⁇ M, 10 ⁇ M, 25 ⁇ M, or 50 M
  • FIG. 9B is a graph of untreated human macrophages (i.e., Untrx), human macrophages stimulated with A ⁇ (1-42) peptides (10 ⁇ M), and human macrophages treated with DMSO (0.1% v/v) or COB-152 (0.01 ⁇ M, 0.05 ⁇ M, 0.1 ⁇ M, 0.5 ⁇ M, 1 ⁇ M, 5 ⁇ M, 10 ⁇ M, or 25 ⁇ M) stimulated with A ⁇ (1-42) peptides (10 ⁇ M) for 5 hours with respect to fold change in IL-6 protein expression (pg/mL);
  • FIG. 9C is a graph of untreated human macrophages (i.e., Untrx), human macrophages stimulated with A ⁇ (1-42) peptides (10 ⁇ M), and human macrophages treated with DMSO (0.1% v/v) or COB-187 (0.01 ⁇ M, 0.05 ⁇ M, 0.1 ⁇ M, 0.5 ⁇ M, 1 ⁇ M, 5 ⁇ M, 10 ⁇ M, or 25 ⁇ M) stimulated with A ⁇ (1-42) peptides (10 ⁇ M) for 5 hours with respect to fold change in IL-6 mRNA expression;
  • FIG. 10B is a graph of untreated human macrophages (i.e., Untrx), human macrophages stimulated with A ⁇ (1-42) peptides (10 ⁇ M), and human macrophages treated with DMSO (0.1% v/v) or COB-152 (0.01 ⁇ M, 0.05 ⁇ M, 0.1 ⁇ M, 0.5 ⁇ M, 1 ⁇ M, 5 ⁇ M, 10 ⁇ M, or 25 ⁇ M) stimulated with A ⁇ (1-42) peptides (10 ⁇ M) for 5 hours with respect to fold change in TNF- ⁇ protein expression (pg/mL);
  • FIG. 10C is a graph of untreated human macrophages (i.e., Untrx), human macrophages stimulated with A ⁇ (1-42) peptides (10 ⁇ M), and human macrophages treated with DMSO (0.1% v/v) or COB-187 (0.01 ⁇ M, 0.05 ⁇ M, 0.1 ⁇ M, 0.5 ⁇ M, 1 ⁇ M, 5 ⁇ M, 10 M, or 25 ⁇ M) stimulated with A ⁇ (1-42) peptides (10 ⁇ M) for 5 hours with respect to fold change in TNF- ⁇ mRNA expression;
  • FIG. 10D is a graph of untreated human macrophages (i.e., Untrx), human macrophages stimulated with A ⁇ (1-42) peptides (10 ⁇ M), and human macrophages treated with DMSO (0.1% v/v) or COB-187 (0.01 ⁇ M, 0.05 ⁇ M, 0.1 ⁇ M, 0.5 ⁇ M, 1 ⁇ M, 5 ⁇ M, 10 M, or 25 ⁇ M) stimulated with A ⁇ (1-42) peptides (10 ⁇ M) for 5 hours with respect to fold change in TNF- ⁇ protein expression (pg/mL);
  • FIG. 11A is a graph of untreated human macrophages (i.e., Untrx), human macrophages stimulated with A ⁇ (1-42) peptides (10 ⁇ M), and human macrophages treated with DMSO (0.1% v/v) or COB-152 (0.01 ⁇ M, 0.05 ⁇ M, 0.1 ⁇ M, 0.5 ⁇ M, 1 ⁇ M, 5 ⁇ M, 10 M, or 25 ⁇ M) stimulated with A ⁇ (1-42) peptides (10 ⁇ M) for 5 hours with respect to fold change in IL-1 ⁇ mRNA expression;
  • FIG. 11B is a graph of untreated human macrophages (i.e., Untrx), human macrophages stimulated with A ⁇ (1-42) peptides (10 ⁇ M), and human macrophages treated with DMSO (0.1% v/v) or COB-152 (0.01 ⁇ M, 0.05 ⁇ M, 0.1 ⁇ M, 0.5 ⁇ M, 1 ⁇ M, 5 ⁇ M, 10 ⁇ M, or 25 ⁇ M) stimulated with A ⁇ (1-42) peptides (10 ⁇ M) for 5 hours with respect to fold change in IL-1 ⁇ protein expression (pg/mL);
  • FIG. 11C is a graph of untreated human macrophages (i.e., Untrx), human macrophages stimulated with A ⁇ (1-42) peptides (10 ⁇ M), and human macrophages treated with DMSO (0.1% v/v) or COB-187 (0.01 ⁇ M, 0.05 ⁇ M, 0.1 ⁇ M, 0.5 ⁇ M, 1 ⁇ M, 5 ⁇ M, 10 ⁇ M, or 25 ⁇ M) stimulated with A ⁇ (1-42) peptides (10 ⁇ M) for 5 hours with respect to fold change in IL-1 ⁇ mRNA expression;
  • FIG. 11D is a graph of untreated human macrophages (i.e., Untrx), human macrophages stimulated with A ⁇ (1-42) peptides (10 ⁇ M), and human macrophages treated with DMSO (0.1% v/v) or COB-187 (0.01 ⁇ M, 0.05 ⁇ M, 0.1 ⁇ M, 0.5 ⁇ M, 1 ⁇ M, 5 ⁇ M, 10 M, or 25 ⁇ M) stimulated with A ⁇ (1-42) peptides (10 ⁇ M) for 5 hours with respect to fold change in IL-1 ⁇ protein expression (pg/mL);
  • FIG. 12A is a graph of untreated human macrophages (i.e., Untrx), human macrophages stimulated with A ⁇ (1-42) peptides (10 ⁇ M), and human macrophages treated with DMSO (0.1% v/v) or COB-152 (0.01 ⁇ M, 0.05 ⁇ M, 0.1 ⁇ M, 0.5 ⁇ M, 1 ⁇ M, 5 ⁇ M, 10 M, or 25 ⁇ M) stimulated with A ⁇ (1-42) peptides (10 ⁇ M) for 5 hours with respect to fold change in IL-1 ⁇ mRNA expression;
  • FIG. 12B is a graph of untreated human macrophages (i.e., Untrx), human macrophages stimulated with A ⁇ (1-42) peptides (10 ⁇ M), and human macrophages treated with DMSO (0.1% v/v) or COB-187 (0.01 ⁇ M, 0.05 ⁇ M, 0.1 ⁇ M, 0.5 ⁇ M, 1 ⁇ M, 5 ⁇ M, 10 ⁇ M, or 25 ⁇ M) stimulated with A ⁇ (1-42) peptides (10 ⁇ M) for 5 hours with respect to fold change in IL-1 ⁇ mRNA expression;
  • FIG. 13A is a graph of untreated human macrophages (i.e., Untrx), human macrophages stimulated with A ⁇ (1-42) peptides (10 ⁇ M), and human macrophages treated with DMSO (0.1% v/v) or COB-152 (0.01 ⁇ M, 0.05 ⁇ M, 0.1 ⁇ M, 0.5 ⁇ M, 1 ⁇ M, 5 ⁇ M, 10 M, or 25 ⁇ M) stimulated with A ⁇ (1-42) peptides (10 ⁇ M) for 5 hours with respect to fold change in IFN- ⁇ mRNA expression;
  • FIG. 13B is a graph of untreated human macrophages (i.e., Untrx), human macrophages stimulated with A ⁇ (1-42) peptides (10 ⁇ M), and human macrophages treated with DMSO (0.1% v/v) or COB-187 (0.01 ⁇ M, 0.05 ⁇ M, 0.1 ⁇ M, 0.5 ⁇ M, 1 ⁇ M, 5 ⁇ M, 10 ⁇ M, or 25 ⁇ M) stimulated with A ⁇ (1-42) peptides (10 ⁇ M) for 5 hours with respect to fold change in IFN- ⁇ mRNA expression;
  • FIG. 14A is a graph of untreated human macrophages (i.e., Untrx), human macrophages stimulated with LPS (10 ng/mL), and human macrophages treated with DMSO (0.1% v/v) or COB-152 (0.01 ⁇ M, 0.05 ⁇ M, 0.1 ⁇ M, 0.5 ⁇ M, 1 ⁇ M, 5 ⁇ M, 10 ⁇ M, 25 ⁇ M, or 50 ⁇ M) stimulated with LPS (10 ng/mL) for 5 hours with respect to fold change in IL-6 mRNA expression;
  • FIG. 14B is a graph of untreated human macrophages (i.e., Untrx), human macrophages stimulated with LPS (10 ng/mL), and human macrophages treated with DMSO (0.1% v/v) or COB-152 (0.01 ⁇ M, 0.05 ⁇ M, 0.1 ⁇ M, 0.5 ⁇ M, 1 ⁇ M, 5 ⁇ M, 10 ⁇ M, 25 ⁇ M, or 50 ⁇ M) stimulated with LPS (10 ng/mL) for 5 hours with respect to fold change in IL-6 protein expression (pg/mL);
  • FIG. 14C is a graph of untreated human macrophages (i.e., Untrx), human macrophages stimulated with LPS (10 ng/mL), and human macrophages treated with DMSO (0.1% v/v) or COB-187 (0.01 ⁇ M, 0.05 ⁇ M, 0.1 ⁇ M, 0.5 ⁇ M, 1 ⁇ M, 5 ⁇ M, 10 ⁇ M, 25 ⁇ M, or 50 ⁇ M) stimulated with LPS (10 ng/mL) for 5 hours with respect to fold change in IL-6 mRNA expression;
  • FIG. 14D is a graph of untreated human macrophages (i.e., Untrx), human macrophages stimulated with LPS (10 ng/mL), and human macrophages treated with DMSO (0.1% v/v) or COB-187 (0.01 ⁇ M, 0.05 ⁇ M, 0.1 ⁇ M, 0.5 ⁇ M, 1 ⁇ M, 5 ⁇ M, 10 ⁇ M, 25 ⁇ M, or 50 ⁇ M) stimulated with LPS (10 ng/mL) for 5 hours with respect to fold change in IL-6 protein expression (pg/mL);
  • FIG. 15B is a graph of untreated human macrophages (i.e., Untrx), human macrophages stimulated with LPS (10 ng/mL), and human macrophages treated with DMSO (0.1% v/v) or COB-152 (0.01 ⁇ M, 0.05 ⁇ M, 0.1 ⁇ M, 0.5 ⁇ M, 1 ⁇ M, 5 ⁇ M, 10 ⁇ M, 25 ⁇ M, or 50 ⁇ M) stimulated with LPS (10 ng/mL) for 5 hours with respect to fold change in TNF- ⁇ protein expression (pg/mL);
  • FIG. 15C is a graph of untreated human macrophages (i.e., Untrx), human macrophages stimulated with LPS (10 ng/mL), and human macrophages treated with DMSO (0.1% v/v) or COB-187 (0.01 ⁇ M, 0.05 ⁇ M, 0.1 ⁇ M, 0.5 ⁇ M, 1 ⁇ M, 5 ⁇ M, 10 ⁇ M, 25 ⁇ M, or 50 ⁇ M) stimulated with LPS (10 ng/mL) for 5 hours with respect to fold change in TNF- ⁇ mRNA expression;
  • FIG. 15D is a graph of untreated human macrophages (i.e., Untrx), human macrophages stimulated with LPS (10 ng/mL), and human macrophages treated with DMSO (0.1% v/v) or COB-187 (0.01 ⁇ M, 0.05 ⁇ M, 0.1 ⁇ M, 0.5 ⁇ M, 1 ⁇ M, 5 ⁇ M, 10 ⁇ M, 25 ⁇ M, or 50 ⁇ M) stimulated with LPS (10 ng/mL) for 5 hours with respect to fold change in TNF- ⁇ protein expression (pg/mL);
  • FIG. 16A is a graph of untreated human macrophages (i.e., Untrx), human macrophages stimulated with LPS (10 ng/mL), and human macrophages treated with DMSO (0.1% v/v) or COB-152 (0.01 ⁇ M, 0.05 ⁇ M, 0.1 ⁇ M, 0.5 ⁇ M, 1 ⁇ M, 5 ⁇ M, 10 ⁇ M, 25 ⁇ M, or 50 ⁇ M) stimulated with LPS (10 ng/mL) for 5 hours with respect to fold change in IL-1 ⁇ mRNA expression;
  • FIG. 16B is a graph of untreated human macrophages (i.e., Untrx), human macrophages stimulated with LPS (10 ng/mL), and human macrophages treated with DMSO (0.1% v/v) or COB-152 (0.01 ⁇ M, 0.05 ⁇ M, 0.1 ⁇ M, 0.5 ⁇ M, 1 ⁇ M, 5 ⁇ M, 10 ⁇ M, 25 ⁇ M, or 50 ⁇ M) stimulated with LPS (10 ng/mL) for 5 hours with respect to fold change in IL-1 ⁇ protein expression (pg/mL);
  • FIG. 16C is a graph of untreated human macrophages (i.e., Untrx), human macrophages stimulated with LPS (10 ng/mL), and human macrophages treated with DMSO (0.1% v/v) or COB-187 (0.01 ⁇ M, 0.05 ⁇ M, 0.1 ⁇ M, 0.5 ⁇ M, 1 ⁇ M, 5 ⁇ M, 10 ⁇ M, 25 ⁇ M, or 50 ⁇ M) stimulated with LPS (10 ng/mL) for 5 hours with respect to fold change in IL-1 ⁇ mRNA expression;
  • FIG. 16D is a graph of untreated human macrophages (i.e., Untrx), human macrophages stimulated with LPS (10 ng/mL), and human macrophages treated with DMSO (0.1% v/v) or COB-187 (0.01 ⁇ M, 0.05 ⁇ M, 0.1 ⁇ M, 0.5 ⁇ M, 1 ⁇ M, 5 ⁇ M, 10 ⁇ M, 25 ⁇ M, or 50 ⁇ M) stimulated with LPS (10 ng/mL) for 5 hours with respect to fold change in IL-1 ⁇ protein expression (pg/mL);
  • FIG. 17A is a graph of untreated human macrophages (i.e., Untrx), human macrophages stimulated with LPS (10 ng/mL), and human macrophages treated with DMSO (0.1% v/v) or COB-152 (0.01 ⁇ M, 0.05 ⁇ M, 0.1 ⁇ M, 0.5 ⁇ M, 1 ⁇ M, 5 ⁇ M, 10 ⁇ M, 25 ⁇ M, or 50 ⁇ M) stimulated with LPS (10 ng/mL) for 5 hours with respect to fold change in IL-1 ⁇ mRNA expression;
  • FIG. 18 is a graph of untreated murine macrophages, murine macrophages stimulated with LPS, and murine macrophages treated with DMSO, macrophages treated with COB-152 (0.1 ⁇ M, 1 ⁇ M, or 10 ⁇ M) with respect to iNOS fold expression.
  • the terms “modulate”, “modulation”, and “modulating” refer to reducing, terminating, and/or enhancing activity of an enzyme, such as, e.g., GSK-3 activity.
  • the terms “modulate”, “modulation”, and “modulating” refer to preventing, reducing, enhancing and/or terminating the expression and/or function of messenger molecules in a signaling pathway.
  • imidazole and/or thiazole compounds may be effective to modulate signaling of GSK-3 by preventing, reducing, enhancing, and/or terminating expression and/or function of messenger molecules upstream and/or downstream of GSK-3.
  • imidazole and/or thiazole compounds may be effective to modulate signaling of GSK-3 by enhancing expression of ⁇ -catenin, inhibiting function of lipopolysaccharide, and/or suppressing expression of i-Nitrous Oxide Synthase.
  • the terms “inhibit”, “inhibition”, and “inhibiting” refer to reducing and/or terminating activity of an enzyme, such as, e.g., GSK-3 activity.
  • an enzyme such as, e.g., GSK-3 activity.
  • imidazole and/or thiazole compounds recognize, bind to, and/or otherwise combine with GSK-3 in a way that influences the binding of GSK-3 substrates thereto and/or in a way that influences the turnover number of GSK-3.
  • the term “inhibit”, “inhibition”, and “inhibiting” refer to preventing and/or terminating the expression and/or function of signaling molecules in a signaling pathway.
  • GSK-3 refers to the enzyme glycogen synthase kinase 3 and homologs thereof.
  • enzyme activity refers to a measure of active enzyme, such as, e.g., GSK-3, present. More specifically, in embodiments, enzyme activity refers to the ability of an enzyme to convert a substrate into a product. Quantitatively, enzyme activity refers to moles of substrate converted to product per unit time.
  • therapeutically effective amount refers to an amount necessary or sufficient to realize a desired biologic effect.
  • the therapeutically effective amount may vary depending on a variety of factors known to those of ordinary skill in the art, including but not limited to, the particular composition being administered, the activity of the composition being administered, the size of the subject, the sex of the subject, the age of the subject, the general health of the subject, the timing and route of administration, the rate of excretion, the administration of additional medications, and/or the severity of the disease or disorder being prevented and/or treated.
  • the term therapeutically effective amount refers to the amount of imidazole and/or thiazole compounds and, more specifically, imidazole 2-thiones, imidazole 2-ones, thiazole 2-thiones, and/or thiazole 2-ones, necessary or sufficient to inhibit GSK-3 activity, to modulate GSK-3 signaling, and/or to treat GSK-3-mediated disorders and/or diseases.
  • imidazole compounds and/or “thiazole compounds”, as used herein, refer to and/or are limited to the compositions having the following general structural formulae:
  • R 1 is chosen from C 1 to C 10 aliphatic or heteroaliphatic groups, the C 1 to C 10 aliphatic or heteroaliphatic groups being substituted with one or more heteroaryl groups, substituted heteroaryl groups, or combination thereof;
  • R 2 is chosen from aromatic moieties, substituted aromatic moieties, heteroaromatic moieties, substituted heteroaromatic moieties, and coumarin;
  • R 3 is chosen from —H, C 1 to C 10 aliphatic or heteroaliphatic groups, phenyl, or substituted phenyl, wherein the aliphatic or heteroaliphatic groups are optionally substituted with one or more phenyl groups, aryl groups, heteroaryl groups, substituted heteroaryl groups, or combination thereof;
  • X is S or O; and
  • Y is S or NH, with the proviso that when R 2 is phenyl and R 3 is —H, at least one
  • group R 1 is chosen from C 1 to C 10 aliphatic or heteroaliphatic groups, optionally substituted with one or more aryl groups, substituted aryl groups, heteroaryl groups, substituted heteroaryl groups, or combination thereof.
  • group R 1 is chosen from methyl, ethyl, propyl, butyl, pentyl, hexyl, 2-propenyl,
  • group R 1 may have be a group QP:
  • groups R 4 , R 5 , and R 6 are independently chosen from —H, halo (such as —F, —Cl, or —Br), —NO 2 , —CN, or alkylesters such as —OCH 3 .
  • group R 1 may be a group Q 1 , in which groups R 4 and R 5 all are H and group R 6 is chosen from alkylesters, Cl, —NO 2 , or —CN.
  • group R 2 is chosen from unsubstituted aryl groups, substituted aryl groups, heteroaryl groups, substituted heteroaryl groups, and coumarin.
  • group R 2 may be an unsubstituted phenyl group, a 2-monosubstituted phenyl group, a 3-monosubstituted phenyl group, a 4-monosubstituted phenyl group, a 2,3-disubstituted phenyl group, a 2,4-disubstituted phenyl group, a 2,5-disubstituted phenyl group, a 3,4-disubstituted phenyl group, or a 3,5-disubstituted phenyl group.
  • group R 2 may be a group Q 2 :
  • group R 2 is a monosubstituted phenyl group Q 2
  • group Q 2 in group Q 2 exactly three of any of R 7 , R 8 , R 9 , and R 1′ are hydrogen, and the one of R 7 , R 8 , R 9 , and R 1′ that is not hydrogen may be chosen from methoxy, ethoxy, hydroxy, trifluoromethoxy, methyl, trifluoromethyl, N-methylamino, (N,N)-dimethylamino, cyano, halo (for example, chloro, fluoro, or bromo), or nitro, for example.
  • group R 2 is a disubstituted phenyl group Q 2
  • group Q 2 in group Q 2 exactly two of any of R 7 , R 8 , R 9 , and R 10 are hydrogen, and the two groups of R 7 , R 8 , R 9 , and R 10 that are not hydrogen may be independently chosen from methoxy, ethoxy, hydroxy, trifluoromethoxy, dimethylamino, cyano, chloro, fluoro, or nitro, for example.
  • group Q 2 may be any isomer of hydroxyphenyl, dihydroxyphenyl, methoxyphenyl, dimethoxyphenyl, halophenyl, dihalophenyl, chlorophenyl, dichlorophenyl, fluorophenyl, halohydroxyphenyl, halomethoxyphenyl, chlorohydroxylphenyl, chloromethoxyphenyl, fluorohydroxyphenyl, fluoromethoxyphenyl.
  • group R 2 as a monosubstituted phenyl group Q 2 or a disubstituted phenyl group Q 2 may include 2-methoxyphenyl; 3-methoxyphenyl; 3-chlorophenyl; 2,5-dimethoxyphenyl; 2,4-dimethoxyphenyl; 3,4-dimethoxyphenyl; 4-(dimethylamino)phenyl; 4-(trifluoromethoxy)phenyl; 4-cyanophenyl; 3-hydroxyphenyl; 2,4-hydroxyphenyl; 3,4-dichlorophenyl; 3-nitrophenyl; 2-hydroxy-5-chlorophenyl; 2-methylphenyl; 2,5-dimethylphenyl; 2-methoxy-5-fluorophenyl; and 2-chloro-5-(trifluoromethyl)phenyl.
  • group R 2 may be an aryl group such as, for example,
  • group R 2 may be an aryl group other than phenyl. In other embodiments, group R 2 may be a heteroaryl group such as, for example,
  • group R 2 may be coumarin, such as, for example,
  • preferred compounds of General Formula (I) and General Formula (II) may include compounds of formulas (III)-(VIII):
  • group R 3 is chosen from —H, C 1 to C 10 aliphatic or heteroaliphatic groups, phenyl, or substituted phenyl, wherein the aliphatic or heteroaliphatic groups are optionally substituted with one or more phenyl groups, aryl groups, heteroaryl groups, substituted heteroaryl groups, or combination thereof.
  • R 3 may be methyl, ethyl, n-propyl, isopropyl, butyl, 3-butenyl, phenyl, or 2-phenylethyl.
  • R 3 is hydrogen.
  • the aliphatic or heteroaliphatic groups of R 3 optionally may be bonded to group R 2 to form a ring.
  • One illustrative example of an aliphatic group R 3 bonded to group R 2 to form a ring is the structure
  • group R 1 attached to the nitrogen atom is phenylmethyl (benzyl)
  • group R 2 is phenyl
  • group R 3 is an ethyl group bonded to the 2-position of the phenyl ring of R 2 to form a six-membered ring including all of group R 3 and part of group R 2 .
  • X is S or O; and Y is S or NH.
  • group X is S and group Y is S.
  • group X is S and group Y is NH.
  • group X is O and group Y is S.
  • group X is O and group Y is NH.
  • the compounds of General Formula (I) and General Formula (II) may be prepared using any suitable synthetic scheme.
  • the compounds having General Formula (I) in which X ⁇ O or S and Y ⁇ NH may be synthesized by adding an isothiocyanate or isocyanate of formula (1a):
  • the reaction mixture may be heated at a suitable reaction temperature for a suitable time. If the heating is accomplished using microwave irradiation, the rate of elimination of a hydroxyl group from the product is increased, so as to substantially favor formation of compounds of General Formula (I) over those of General Formula (II). Conversely, application of heat without microwave irradiation favors compounds of General Formula (II) as products.
  • the solvent may be removed, and the product may be isolated by flash chromatography, for example.
  • a crude reaction mixture may be extracted with a solvent such as ethyl acetate, and the combined organic layers may be dried and filtered.
  • the solvent may be evaporated by rotary evaporation.
  • the product may be isolated using a solvent such as 10%-20% EtOAc in hexanes. In some cases, some products may precipitate during the reaction. In such cases the product may be isolated by filtration, washed thoroughly with solvent, then dried.
  • the compounds of General Formula (I) and General Formula (II) may be generally described as a class of compounds composed of four genera: (1) imidazole 2-thiones (in which group X is S and group Y is NH); (2) imidazole 2-ones (in which group X is O and group Y is NH); (3) thiazole 2-thiones (in which group X is S and group Y is S); and (4) thiazole 2-ones (in which group X is O and group Y is S).
  • R 1 is a C 1 to C 10 aliphatic or heteroaliphatic group that is substituted with at least one substituted aryl group, at least one heteroaryl group, at least one substituted heteroaryl group, or combination thereof;
  • R 1 is hexyl; or
  • R 1 is Ph(CH 2 ) n —, where n is 2 or 3 (i.e., group R 1 is 2-phenylethyl or 3-phenylpropyl); or
  • R 1 is a C 1 to C 10 heteroaliphatic group, optionally substituted with one or more aryl groups, substituted aryl groups, heteroaryl groups, substituted heteroaryl groups, or combination thereof.
  • compounds of General Formula (I) and General Formula (II) do not include compounds in which group R 2 is phenyl and R 3 is hydrogen, at least one of the following is true: (a) R 1 is a C 1 to C 10 aliphatic or heteroaliphatic group that is substituted with at least one substituted aryl
  • C 1 to C 10 aliphatic groups R 1 do not include aliphatic groups substituted with aryl groups that themselves are not substituted(such as phenyl), with the exception from proviso (c) that R 1 may be 2-phenylethyl or 3-phenylpropyl. In view of proviso (d), however, even when R 2 is phenyl and R 3 is hydrogen, C 1 to C 10 heteroaliphatic groups R 1 may be unsubstituted or substituted.
  • imidazole 2-thiones refers to compositions having the general structural formula (I) and/or general structural formula (II) as described above, in which group X is S and group Y is NH.
  • imidazole 2-ones refers to compositions having the general structural formula (I) and/or general structural formula (II) as described above, in which group X is O and group Y is NH.
  • thiazole 2-thiones refers to compositions having the general structural formula (I) and/or general structural formula (II) as described above, in which group X is S and group Y is S.
  • thiazole 2-ones refers to compositions having the general structural formula (I) and/or general structural formula (II) as described above, in which group X is O and group Y is S.
  • aliphatic includes both saturated and unsaturated, straight chain (i.e., unbranched) or branched aliphatic hydrocarbons, which are optionally substituted with one or more functional groups.
  • aliphatic is intended herein to include, but is not limited to, alkyl, alkenyl, alkynyl moieties.
  • alkyl includes straight and branched alkyl groups. An analogous convention applies to other generic terms such as “alkenyl”, “alkynyl” and the like.
  • alkyl encompass both substituted and unsubstituted groups.
  • lower alkyl may be used to indicate alkyl groups (substituted, unsubstituted, branched or unbranched) having from 1 to 6 carbon atoms.
  • the alkyl, alkenyl, and alkynyl groups described herein contain from 1 to 10 aliphatic carbon atoms. In other embodiments, the alkyl, alkenyl, and alkynyl groups described herein contain from 1 to 8 aliphatic carbon atoms. In still other embodiments, the alkyl, alkenyl, and alkynyl groups described herein contain from 1 to 6 aliphatic carbon atoms. In yet other embodiments, the alkyl, alkenyl, and alkynyl groups described herein contain from 1 to 4 carbon atoms.
  • Illustrative aliphatic groups thus include, but are not limited to, for example, methyl, ethyl, n-propyl, isopropyl, allyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, sec-pentyl, isopentyl, tert-pentyl, n-hexyl, sec-hexyl, moieties and the like, which optionally may bear one or more substituents.
  • Alkenyl groups include, but are not limited to, for example, ethenyl, propenyl, butenyl, 1-methyl-2-buten-1-yl, and the like.
  • Representative alkynyl groups include, but are not limited to, ethynyl, 2-propynyl (propargyl), 1-propynyl and the like.
  • alicyclic refers to compounds which combine the properties of aliphatic and cyclic compounds and include but are not limited to monocyclic, or polycyclic aliphatic hydrocarbons and bridged cycloalkyl compounds, which are optionally substituted with one or more functional groups.
  • alicyclic is intended herein to include, but is not limited to, cycloalkyl, cycloalkenyl, and cycloalkynyl moieties, which are optionally substituted with one or more functional groups.
  • Illustrative alicyclic groups thus include, but are not limited to, for example, cyclopropyl, —CH 2 -cyclopropyl, cyclobutyl, —CH 2 -cyclobutyl, cyclopentyl, —CH 2 -cyclopentyl, cyclohexyl, —CH 2 -cyclohexyl, cyclohexenylethyl, cyclohexanylethyl, norbornyl moieties and the like, which optionally may bear one or more substituents.
  • alkoxy refers to a saturated (i.e., O-alkyl) or unsaturated (i.e., O-alkenyl and O-alkynyl) group attached to the parent molecular moiety through an oxygen atom.
  • the alkyl group contains from 1 to 10 aliphatic carbon atoms.
  • the alkyl group contains from 1 to 8 aliphatic carbon atoms.
  • the alkyl group contains from 1 to 6 aliphatic carbon atoms.
  • the alkyl group contains from 1 to 4 aliphatic carbon atoms.
  • alkoxy examples include but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, i-butoxy, sec-butoxy, tert-butoxy, neopentoxy, n-hexoxy and the like.
  • alkylamino refers to a group having the structure —NHR′ wherein R′ is alkyl, as defined herein.
  • aminoalkyl refers to a group having the structure NH 2 R′—, wherein R′ is alkyl, as defined herein.
  • the alkyl group contains from 1 to 10 aliphatic carbon atoms.
  • the alkyl groups contain from 1 to 8 aliphatic carbon atoms.
  • the alkyl group contains from 1 to 6 aliphatic carbon atoms.
  • the alkyl group contains from 1 to 4 aliphatic carbon atoms.
  • alkylamino include, but are not limited to, methylamino, ethylamino, isopropylamino and the like.
  • aromatic moiety refers to a stable monocyclic or polycyclic, unsaturated moiety having preferably from 3 to 14 carbon atoms, each of which may be substituted or unsubstituted.
  • aromatic moiety refer to a planar ring having p-orbitals perpendicular to the plane of the ring at each ring atom and satisfying the Hückel rule where the number of pi electrons in the ring is (4n+2), where n is an integer.
  • a monocyclic or polycyclic, unsaturated moiety that does not satisfy one or all of these criteria for aromaticity is defined herein as “non-aromatic” and is encompassed by the term “alicyclic.”
  • heteromatic moiety refers to a stable monocyclic or polycyclic, unsaturated moiety having preferably from 3 to 14 carbon atoms, each of which may be substituted or unsubstituted; and comprising at least one heteroatom selected from O, S, and N within the ring (i.e., in place of a ring carbon atom).
  • heteromatic moiety refers to a planar ring comprising at least one heteroatom, having p-orbitals perpendicular to the plane of the ring at each ring atom, and satisfying the Hückel rule where the number of pi electrons in the ring is (4n+2), where n is an integer.
  • cycloalkyl refers specifically to groups having three to seven, preferably three to ten carbon atoms. Suitable cycloalkyls include, but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like, which, as in the case of aliphatic, alicyclic, heteroaliphatic or heterocyclic moieties, may optionally be substituted with substituents including, but not limited to aliphatic; alicyclic; heteroaliphatic; heterocyclic; aromatic; heteroaromatic; aryl; heteroaryl; alkylaryl; heteroalkylaryl; alkylheteroaryl; heteroalkylheteroaryl; alkoxy; aryloxy; heteroalkoxy; heteroaryloxy; alkylthio; arylthio; heteroalkylthio; heteroarylthio; F; Cl; Br; I; —OH
  • heterocycloalkyl refers to compounds that combine the properties of heteroaliphatic and cyclic compounds and include, but are not limited to, saturated and unsaturated mono- or polycyclic cyclic ring systems having from 5 to 16 atoms, wherein at least one ring atom is a heteroatom selected from O, S, and N (wherein the nitrogen and sulfur heteroatoms may optionally be oxidized), wherein the ring systems are optionally substituted with one or more functional groups, as defined herein.
  • heterocycles include, but are not limited to, heterocycles such as furanyl, thiofuranyl, pyranyl, pyrrolyl, thienyl, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, oxazolyl, oxazolidinyl, isooxazolyl, isoxazolidinyl, dioxazolyl, thiadiazolyl, oxadiazolyl, tetrazolyl, triazolyl, thiatriazolyl, oxatriazolyl, thiadiazolyl, oxadiazolyl, morpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, dithiazolyl, dithiazolidinyl, tetrahydrofuryl
  • a “substituted heterocycle, or heterocycloalkyl or heterocyclic” group refers to a heterocycle, or heterocycloalkyl or heterocyclic group, as defined above, substituted by the independent replacement of one, two or three of the hydrogen atoms thereon with groups including but not limited to aliphatic; alicyclic; heteroaliphatic; heterocyclic; aromatic; hetero aromatic; aryl; heteroaryl; alkylaryl; heteroalkylaryl; alkylheteroaryl; hetero alkylhetero aryl; alkoxy; aryloxy; heteroalkoxy; heteroaryloxy; alkylthio; arylthio; heteroalkylthio; heteroarylthio; F; Cl; Br; I; —OH; —NO 2 ; —CN; —CF 3 ; —CH 2 CF 3 ; —CHCl 2 ; —CH 2 OH; —CH 2 CH 2
  • any of the alicyclic or heterocyclic moieties described above and herein may comprise an aryl or heteroaryl moiety fused thereto. Additional examples of generally applicable substituents are illustrated by the specific embodiments shown in the Examples that are described herein.
  • halo and halogen refer to an atom selected from fluorine, chlorine, bromine and iodine.
  • amino refers to a primary amine (—NH 2 ), a secondary amine (—NHR X ), a tertiary amine (—NR X R Y ), or a quaternary amine (—N+R X R Y R Z ), where R X , R Y , and R Z are independently an aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic or heteroaromatic moiety, as defined herein.
  • amino groups include, but are not limited to, methylamino, dimethylamino, ethylamino, diethylamino, diethylaminocarbonyl, methylethylamino, isopropylamino, piperidino, trimethylamino, and propylamino.
  • C 1 -C 6 alkylidene refers to a substituted or unsubstituted, linear or branched, saturated divalent radical consisting solely of carbon and hydrogen atoms, having from one to six carbon atoms, having a free valence “-” at both ends of the radical.
  • C 2 -C 6 alkenylidene refers to a substituted or unsubstituted, linear or branched, unsaturated divalent radical consisting solely of carbon and hydrogen atoms, having from two to six carbon atoms, having a free valence “-” at both ends of the radical, and wherein the unsaturation is present only as double bonds and wherein a double bond can exist between the first carbon of the chain and the rest of the molecule.
  • aliphatic As used herein, the terms “aliphatic,” “heteroaliphatic,” “alkyl,” “alkenyl,” “alkynyl,” “heteroalkyl,” “heteroalkenyl,” “heteroalkynyl,” and the like encompass substituted and unsubstituted, saturated and unsaturated, and linear and branched groups. Similarly, the terms “alicyclic,” “heterocyclic,” “heterocycloalkyl,” “heterocycle” and the like encompass substituted and unsubstituted, and saturated and unsaturated groups.
  • cycloalkyl encompass both substituted and unsubstituted groups.
  • salts derived from inorganic bases include: aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc, and the like. Particularly preferred are the ammonium, calcium, magnesium, potassium, and sodium salts.
  • Salts derived from pharmaceutically acceptable organic non-toxic bases include: salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as arginine, betaine, caffeine, choline, N,N′-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethyl-morpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like.
  • basic ion exchange resins such
  • salts may be prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids.
  • acids include: acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid, and the like.
  • compositions include but are not limited to acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium edetate, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexyl-resorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate,
  • solvate or “salt solvated” refers to a complex of variable stoichiometry formed by a solute (such as compounds of Formula (I) or (II) described below (or a salt thereof)) and a solvent. In some embodiments, such solvents do not interfere with the biological activity of the solute.
  • suitable solvents include, but are not limited to, water, methanol, ethanol and acetic acid.
  • the solvent is a pharmaceutically acceptable solvent.
  • suitable pharmaceutically acceptable solvents include, without limitation, water, ethanol, and acetic acid. In one particular embodiment, the solvent is water, providing a “hydrate.”
  • the term “IC 50 ” refers to an inhibitor concentration at which an enzyme, such as, e.g., GSK-3, exhibits 50% of its maximal activity. In other embodiments, the term ““IC 50 ” refers to an inhibitor concentration at which expression of mRNA and/or protein is inhibited by 50%.
  • treat refers to prophylactically avoiding and/or prolonging the development or acquisition of, reducing the risk of developing, delaying acquisition of, inhibiting the development or progression of, stabilizing, and/or causing regression of a disease, disorder or symptom thereof.
  • GSK-3 mediated disorder refers to a disease and/or condition which relies on the activity of GSK-3 for expression of the disease and/or condition.
  • a GSK-3 mediated disorder may include all diseases and/or conditions relying on the activity of GSK-3 for expression thereof which are treatable with lithium and/or other known GSK-3 inhibitors.
  • a subject in need thereof refers to a subject at risk for developing a disease, disorder, and/or symptom thereof, a subject exhibiting symptoms associated with a disease, disorder, and/or symptom thereof, and/or a subject having a disease, disorder, and/or symptom thereof.
  • a subject in need thereof may include a subject at risk for developing a GSK-3 mediated disorder and/or symptom thereof, a subject exhibiting symptoms associated with a GSK-3 mediated disorder, and/or a subject having a GSK-3 disorder.
  • a subject in need thereof includes a subject having a pathology brought about or cause at least in part by aberrent activity of GSK-3.
  • administer refers to systemic use, such as by injection (e.g., parenterally), intravenous infusion, suppositories and oral administration thereof, and/or to topical use of the imidazole and/or thiazole compounds and, more specifically, imidazole 2-thiones, imidazole 2-ones, thiazole 2-thiones, and/or thiazole 2-ones, and pharmaceutical compositions including the same.
  • the term “compatible” with regard to components of a composition means that components of the composition are capable of being comingled without interacting in a manner which would substantially decrease the efficacy of the pharmaceutically active compound under ordinary use conditions.
  • patient is intended to encompass any mammal, animal or human subject, which may benefit from treatment with the compounds, compositions and methods of the present invention, and includes children and adults.
  • pharmaceutically acceptable refers to a pharmaceutically active agent and/or other agents/ingredients for use in a pharmaceutical composition which are not deleterious to a subject receiving the pharmaceutical composition and/or which are suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like commensurate with a reasonable benefit/risk ratio.
  • the term “pharmaceutical carrier” denotes a solid or liquid filler, diluent or encapsulating substance. These materials are well known to those skilled in the pharmaceutical arts.
  • Some examples of the substances that can serve as pharmaceutical carriers include sugars, such as lactose, glucose, and sucrose; starches, such as corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; powdered tragacanth; malt; gelatin; talc; stearic acid; magnesium stearate; calcium sulfate; vegetable oils, such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil and oil of theobroma ; polyols, such as propylene glycol, glycerine, sorbitol, mannitol, and polyethylene glycol; agar; alginic acid; pyrogen-free water; isotonic saline
  • Embodiments of the present disclosure relate to methods for modulating GSK-3 activity, to methods for modulating GSK-3 signaling, to methods for treating GSK-3 mediated disorders, and to pharmaceutical compositions for GSK-3 activity, modulating GSK-3 signaling, and/or treating GSK-3 mediated disorders.
  • Embodiments of the methods for modulating GSK-3 activity will now be described in detail. Thereafter, embodiments of methods for modulating GSK-3 signaling, methods for treating GSK-3 mediated disorders, and pharmaceutical compositions will be described in detail.
  • the compounds of General Formula (I) and General Formula (II) are believed to modulate, such as, e.g., to inhibit, GSK-3 activity.
  • Methods for modulating, such as, e.g., inhibiting, GSK-3 activity in a cell expressing GSK-3 are disclosed.
  • Such methods may include contacting a cell expressing GSK-3 with a therapeutically effective amount of at least one imidazole and/or thiazole compound (i.e., at least one imidazole compound and/or thiazole compound) and, more specifically, at least one imidazole 2-thione, imidazole 2-one, thiazole 2-thione, and/or thiazole 2-one, to the subject, or pharmaceutically-acceptable salts or solvates thereof.
  • the imidazole and/or thiazole compounds referenced herein are as previously described.
  • the methods include contacting the cell with a therapeutically effective amount of the imidazole and/or thiazole compounds.
  • the method includes contacting the cell with a therapeutically effective amount of COB-152, COB-187, COB-197, and/or COB-198.
  • contacting a cell expressing GSK-3 with a therapeutically effective amount of imidazole and/or thiazole compounds is effective to modulate, such as, e.g., to inhibit, activity of at least one of GSK-3 ⁇ (i.e., GSK-3 alpha) or GSK-3 ⁇ (i.e., GSK-3 beta).
  • contacting the cell expressing GSK-3 with a therapeutically effective amount of the imidazole and/or thiazole compounds modulates the activity of GSK-3 by inhibiting the GSK-3 activity.
  • contacting the cell expressing GSK-3 with the therapeutically effective amount of the imidazole and/or thiazole compounds is effective to inhibit the activity of at least one of GSK-3, including GSK-3 ⁇ and/or GSK-3 ⁇ , by about 20% to about 100%, or by about 30% to about 95%, or by about 40% to about 90%, or by about 50% to about 85%, or by about 60% to about 80%, or by about 75%.
  • the activity of GSK-3 modulated, such as, e.g., inhibited, by the imidazole and/or thiazole compounds is a phosphorylation activity.
  • the imidazole and/or thiazole compounds have an IC 50 value for GSK-3 of from about 100 ⁇ M to about 50 ⁇ M, or from about 1 nM to about 25 ⁇ M, or from about 10 nM to about 10 ⁇ M, or from about 25 nM to about 1 ⁇ M, or from about 50 nM to about 500 nM, or from about 75 nM to about 250 nM, or from about 100 nM to about 200 nM, or about 150 nM.
  • the imidazole and/or thiazole compounds have an IC 50 value for GSK-3 in the nanomolar range.
  • a cell expressing GSK-3 is contacted with imidazole and/or thiazole compounds which are provided in a concentration of from about 100 pM to about 50 ⁇ M, or from about 1 nM to about 25 ⁇ M, or from about 10 nM to about 1 ⁇ M, or from about 50 nM to about 500 nM, or about 75 nM.
  • the imidazole and/or thiazole compounds are specific for GSK-3. More particularly, the imidazole and/or thiazole compounds may be specific for GSK-3 such that the imidazole and/or thiazole compounds preferentially recognize and/or bind to GSK-3 in a complex mixture of proteins, enzymes, and/or macromolecules. In embodiments, the imidazole and/or thiazole compounds preferentially recognize, bind to, and/or otherwise combine with GSK-3 in a complex mixture such that the imidazole and/or thiazole compounds have limited to no effect on non-GSK-3 kinases.
  • the imidazole and/or thiazole compounds preferentially recognize, bind, and/or otherwise combine with GSK-3 such that the activity thereof is inhibited by at least about 75%, and the imidazole and/or thiazole compounds recognize, bind, and/or otherwise combine with non-GSK-3 kinases such that less than about 70% of the activity thereof is inhibited.
  • the imidazole and/or thiazole compounds bind non-GSK-3 kinases such that less than about 50%, or less than about 40%, or less than about 30%, or less than about 20% of the activity thereof is inhibited.
  • the non-GSK-3 kinases are cyclin-dependent protein kinases (i.e., CDK's), including but not limited to, CDK1, CDK2, CDK5/p25, CDK5/p35, CDK7, CDK8, CDK9 Cyclin K, CDK9 Cyclin Ti, and combination thereof.
  • CDK's cyclin-dependent protein kinases
  • the imidazole and/or thiazole compounds have limited to no effect on CDK's, such that upon contact therewith less than about 20% of the activity thereof is inhibited.
  • contacting a cell expressing GSK-3 with the imidazole and/or thiazole compounds is effective to modulate signaling of GSK-3.
  • GSK-3 is involved in a wide range of signal transduction cascades (i.e., signaling pathways) involving cellular processes, including, e.g., glycogen metabolism, cell development, gene transcription, protein translation, cytoskeletal organization, cell cycle regulation, proliferation, and apoptosis.
  • GSK-3 acts as a downstream regulatory switch for numerous signaling pathways, including cellular responses to WNT, growth factors, insulin, receptor tyrosine kinases (i.e., RTK's), Hedgehog pathways, and g-protein coupled receptors (i.e., GPCR's).
  • GSK-3 can be part of a multiprotein complex that includes the proteins axis inhibitor (i.e., AXIN), adenomatous polyposis coli (i.e., APC), casein kinase-1 (i.e., CSNK1), and ⁇ -catenin (i.e., ⁇ -Ctnn). GSK-3 has been shown to phosphorylate ⁇ -catenin, targeting it for ubiquitination and subsequent degradation.
  • proteins axis inhibitor i.e., AXIN
  • APC adenomatous polyposis coli
  • CSNK1 casein kinase-1
  • ⁇ -catenin i.e., ⁇ -Ctnn
  • the imidazole and/or thiazole compounds are effective to modulate signaling of GSK-3 such that phosphorylation of substrates thereof, such as, e.g., ⁇ -catenin, is reduced.
  • contacting a cell expressing GSK-3 with imidazole and/or thiazole compounds is effective to modulate signaling of GSK-3, such that expression of ⁇ -catenin is enhanced (further demonstrating inhibition of GSK-3).
  • contacting a cell expressing GSK-3 with imidazole and/or thiazole compounds is effective to enhance expression of ⁇ -catenin.
  • contacting a cell expressing GSK-3, such as, e.g., a macrophage, with imidazole and/or thiazole compounds is effective to enhance protein expression of ⁇ -catenin.
  • imidazole and/or thiazole compounds may be effective to enhance protein expression of ⁇ -catenin by inhibiting GSK-3 activity at the post-transcriptional level.
  • GSK-3 is also involved in signaling pathways in the innate immune response, including those affecting cytokine production.
  • contacting a cell expressing GSK-3 with thiazole and/or imidazole compounds is effective to modulate signaling of GSK-3 such that immune products of Toll-like receptor (i.e., TLR) signaling, such as, e.g., cytokines, are suppressed.
  • TLR Toll-like receptor
  • GSK-3 has been shown to modulate the function of lipopolysaccharide (i.e., LPS), an inducer of signal transduction events in TLR signaling.
  • LPS lipopolysaccharide
  • imidazole and/or thiazole compounds are effective to modulate signaling of GSK-3 such that function of LPS and/or AP is inhibited. More particularly, in embodiments, imidazole and/or thiazole compounds are effective to modulate signaling of GSK-3 such that LPS- and/or AP-induced expression of reactive products (e.g., cytokines), such as, e.g., expression of i-nitric oxide synthase (i.e., iNOS), Interleukin 6, (i.e., IL-6), Tumor Necrosis Factor- ⁇ (i.e., TNF- ⁇ ), Interleukin 1 ⁇ (i.e., IL-1 ⁇ ), Interleukin 1 ⁇ (i.e., IL-1 ⁇ ), Interferon ⁇ (i.e., IFN- ⁇ ), and/or Interferon ⁇ (i.e., IFN- ⁇ ) is inhibited.
  • reactive products e.g., cytokines
  • the imidazole and/or thiazole compounds are effective to modulate signaling of GSK-3 such that expression, such as, e.g., LPS- and/or AP-induced expression, of iNOS, IL-6, TNF- ⁇ , IL-1 ⁇ , IL-1 ⁇ , IFN- ⁇ , and/or IFN- ⁇ is suppressed.
  • the imidazole and/or thiazole compounds are effective to inhibit LPS-induced and/or A ⁇ -induced expression of reactant products to suppress expression of iNOS, IL-6, and TNF- ⁇ .
  • such suppression of reactive products is effected by imidazole and/or thiazole compounds in a dose-dependent manner.
  • Such suppression of reactive products may be observed via suppression of mRNA and/or protein expression thereof.
  • the methods for modulating, such as, e.g., inhibiting, GSK-3 activity are performed by contacting a sample having a cell expressing GSK-3 with a therapeutically effective amount of imidazole and/or thiazole compounds.
  • the methods for modulating GSK-3 activity are performed by contacting the cell expressing GSK-3 with a therapeutically effective amount of the imidazole and/or thiazole compounds in vitro and/or ex vivo.
  • the cells expressing GSK-3 employed in the methods disclosed herein include eukaryotic cells (as GSK-3 may be ubiquitously expressed in all eukaryotes).
  • the cells expressing GSK-3 employed in the methods disclosed herein include mammalian cells. More specifically, cells expressing GSK-3 may be human, non-human primate, canine, feline, murine, bovine, equine, porcine, and/or lagomorph.
  • the methods for inhibiting cells expressing GSK-3 are performed by contacting at least one of solid tumor cells, blood cancer cells, leukocytes (e.g., macrophages and/or lymphocytes), hepatocytes, endothelial cells, adipocytes, skeletal muscle cells, or pancreatic cells with a therapeutically effective amount of the imidazole and/or thiazole compounds.
  • the methods for modulating, such as, e.g., inhibiting, GSK-3 activity are performed by contacting a cell expressing GSK-3 with a therapeutically effective amount of the imidazole and/or thiazole compounds in vivo.
  • the imidazole and/or the thiazole compounds may be administered to a subject in need thereof.
  • Embodiments of the methods for modulating, such as, e.g., inhibiting, GSK-3 activity have been described in detail. Further embodiments directed to methods for modulating GSK-3 signaling will now be described.
  • the compounds of General Formula (I) and General Formula (II) are believed to modulate, such as, e.g., to inhibit, GSK-3 signaling.
  • Methods for modulating GSK-3 signaling in a cell expressing GSK-3 are disclosed.
  • Such methods may include contacting a cell expressing GSK-3 with a therapeutically effective amount of at least one imidazole and/or thiazole compound (i.e., at least one imidazole compound and/or thiazole compound) and, more specifically, at least one imidazole 2-thione, imidazole 2-one, thiazole 2-thione, and/or thiazole 2-one, to the subject, or pharmaceutically-acceptable salts or solvates thereof.
  • the imidazole and/or thiazole compounds referenced herein are as previously described.
  • the methods include contacting the cell with a therapeutically effective amount of the imidazole and/or thiazole compounds.
  • the method includes contacting the cell with a therapeutically effective amount of COB-152, COB-187, COB-197, and/or COB-198.
  • a cell expressing GSK-3 is contacted with imidazole and/or thiazole compounds which are provided in a concentration of from about 100 pM to about 50 ⁇ M, or from about 1 nM to about 25 ⁇ M, or from about 10 nM to about 1 ⁇ M, or from about 50 nM to about 500 nM, or about 75 nM.
  • contacting a cell expressing GSK-3 with the imidazole and/or thiazole compounds is effective to modulate signaling of GSK-3, as previously described, such as, e.g., in the various signaling cascades in which GSK-3 is involved.
  • the imidazole and/or thiazole compounds are effective to modulate signaling of GSK-3 such that phosphorylation of substrates thereof, such as, e.g., ⁇ -catenin, is reduced.
  • contacting a cell expressing GSK-3 with imidazole and/or thiazole compounds is effective to modulate signaling of GSK-3 such that expression of ⁇ -catenin is enhanced (further demonstrating inhibition of GSK-3).
  • the imidazole and/or thiazole compounds are effective to modulate signaling of GSK-3 such that expression of iNOS, IL-6, TNF- ⁇ , IL-3, IL-1 ⁇ , IFN- ⁇ , and/or IFN- ⁇ is suppressed.
  • such suppression of reactive products e.g., cytokines
  • imidazole and/or thiazole compounds in a dose-dependent manner.
  • Such suppression of reactive products may be observed via suppression of mRNA and/or protein expression thereof.
  • the methods for modulating GSK-3 signaling are performed by contacting a cell expressing GSK-3 with a therapeutically effective amount of the imidazole and/or thiazole compounds in vivo.
  • the imidazole and/or the thiazole compounds may be administered to a subject in need thereof.
  • Such methods may include administering a therapeutically effective amount of at least one imidazole and/or thiazole compound and, more specifically, at least one imidazole 2-thione, imidazole 2-one, thiazole 2-thione, and/or thiazole 2-one, to the subject, or pharmaceutically-acceptable salts or solvates thereof, wherein administration of the imidazole and/or thiazole compound is effective to treat the GSK-3 mediated disorder.
  • the imidazole and/or thiazole compounds referenced herein are as previously described.
  • the method includes administering imidazole and/or thiazole compounds to the subject.
  • the method includes administering a therapeutically effective amount of COB-152, COB-187, COB-197, and/or COB-198 to the subject.
  • GSK-3 plays a vital role in signal transduction activity, wherein it is involved in a wide range of signal transduction cascades involving cellular processes, including, e.g., glycogen metabolism, cell development, gene transcription, protein translation, cytoskeletal organization, cell cycle regulation, proliferation, and apoptosis.
  • GSK-3 is germane to a plethora of cellular processes. Consequently, dysfunctional GSK-3 is a component of a host of pathological processes, as well as a major therapeutic target.
  • GSK-3 was first identified as a serine/threonine kinase regulating glycogen synthase (i.e., GS) via phosphorylation causing inactivation thereof (thus having a role in glucose metabolism), GSK-3 has since been identified as a kinase for over 40 proteins and has been shown to play a role in numerous cellular and/or physiological processes, such as, e.g., embryogenesis, inflammation, and neuroplasticity.
  • aberrant GSK-3 activity has been implicated in a variety of disorders and/or diseases, including but not limited to, malaria, cancer, insulin resistance, type 2 diabetes mellitus, muscle wasting, neurodegenerative diseases, cardiovascular diseases, myocardial diseases, pathological inflammation, bone diseases, renal diseases, HIV-related neurological disorders, horse colic, sepsis, and shock.
  • aberrant GSK-3 activity has also been implicated in psychiatric and central nervous system (i.e., CNS) diseases.
  • CNS central nervous system
  • the imidazole and/or thiazole compounds described herein are effective to treat GSK-3 mediated disorders and/or diseases chosen from malaria, cancer, insulin resistance, type 2 diabetes mellitus, muscle wasting (i.e., muscle atrophy), neurodegenerative disease, cardiovascular disease, myocardial disease, pathological inflammation, bone disease, renal disease, human immunodeficiency virus (i.e., HIV)-related neurological disorder, sepsis, toxic shock, psychiatric disease, CNS disease, or combination thereof.
  • GSK-3 mediated disorders and/or diseases chosen from malaria, cancer, insulin resistance, type 2 diabetes mellitus, muscle wasting (i.e., muscle atrophy), neurodegenerative disease, cardiovascular disease, myocardial disease, pathological inflammation, bone disease, renal disease, human immunodeficiency virus (i.e., HIV)-related neurological disorder, sepsis, toxic shock, psychiatric disease, CNS disease, or combination thereof.
  • the imidazole and/or thiazole compounds described herein are effective to treat GSK-3 mediated disorders, wherein the GSK-3 mediated disorder is a cancer chosen from leukemia, pancreatic cancer, multiple myeloma, glioblastoma, or combination thereof.
  • the imidazole and/or thiazole compounds are effective to treat GSK-3 mediated disorders, wherein the GSK-3 mediated disorder is a leukemia chosen from acute myeloid leukemia (i.e., AML), chronic myeloid leukemia (i.e., CML), acute lymphocytic leukemia (i.e., ALL), chronic lymphocytic leukemia (i.e., CLL), or combination thereof.
  • the imidazole and/or thiazole compounds are effective to treat GSK-3 mediated disorders, wherein the GSK-3 mediated disorder is acute lymphoblastic leukemia.
  • the imidazole and/or thiazole compounds are effective to treat GSK-3 mediated disorders, wherein the GSK-3 mediated disorder is a pancreatic cancer chosen from exocrine group pancreatic cancer, endocrine group pancreatic cancer, or combination thereof.
  • the imidazole and/or thiazole compounds are effective to treat GSK-3 mediated disorders, wherein the GSK-3 mediated disorder is an exocrine group pancreatic cancer chosen from pancreatic adenocarcinoma, acinar cell carcinoma of the pancreas, cystadenocarcinomas, pancreatoblastoma, pancreatic mucinous cystic neoplasms, or combination thereof.
  • the imidazole and/or thiazole compounds are effective to treat GSK-3 mediated disorders, wherein the GSK-3 mediated disorder is a pancreatic neuroendocrine tumor (i.e., PET).
  • the imidazole and/or thiazole compounds are effective to treat GSK-3 mediated disorders, wherein the GSK-3 mediated disorder is multiple myeloma. In yet other embodiments, the imidazole and/or thiazole compounds are effective to treat GSK-3 mediated disorders, wherein the GSK-3 mediated disorder is glioblastoma.
  • the imidazole and/or thiazole compounds described herein are effective to treat GSK-3 mediated disorders, wherein the GSK-3 mediated disorder is a neurodegenerative disease chosen from Parkinson's Disease, Alzheimer's Disease, Huntington's Disease, amyotrophic lateral sclerosis (i.e., ALS), or combination thereof.
  • GSK-3 mediated disorder is a neurodegenerative disease chosen from Parkinson's Disease, Alzheimer's Disease, Huntington's Disease, amyotrophic lateral sclerosis (i.e., ALS), or combination thereof.
  • the imidazole and/or thiazole compounds described herein are effective to treat GSK-3 mediated disorders, wherein the GSK-3 mediated disorder is a cardiovascular disease chosen from atherosclerosis, cardiac ischemia, cardiac reperfusion injury, cardiac hypertrophy, or combination thereof.
  • the imidazole and/or thiazole compounds described herein are effective to treat GSK-3 mediated disorders, wherein the GSK-3 mediated disorder is chosen from cardiac hypertrophy, rheumatic heart disease, hypertensive heart disease, ischemic heart disease (i.e., coronary artery disease), cerebrovascular disease, inflammatory heart disease, atherosclerosis, ischemia, reperfusion injury, coronary artery disease, peripheral artery disease, carotid artery disease, myocarditis, inflammation of the myocardium, or combination thereof.
  • the GSK-3 mediated disorder is chosen from cardiac hypertrophy, rheumatic heart disease, hypertensive heart disease, ischemic heart disease (i.e., coronary artery disease), cerebrovascular disease, inflammatory heart disease, atherosclerosis, ischemia, reperfusion injury, coronary artery disease, peripheral artery disease, carotid artery disease, myocarditis, inflammation of the myocardium, or combination thereof.
  • the imidazole and/or thiazole compounds described herein are effective to treat GSK-3 mediated disorders, wherein the GSK-3 mediated disorder is a pathological inflammation chosen from acne, asthma, autoimmune diseases, autoinflammatory diseases, celiac disease, chronic prostatitis, glomerulonephritis, hypersensitivities, inflammatory bowel diseases, pelvic inflammatory diseases, reperfusion injury, rheumatoid arthritis, sarcoidosis, transplant rejection, vasculitis, interstitial cystitis, or combination thereof.
  • a pathological inflammation chosen from acne, asthma, autoimmune diseases, autoinflammatory diseases, celiac disease, chronic prostatitis, glomerulonephritis, hypersensitivities, inflammatory bowel diseases, pelvic inflammatory diseases, reperfusion injury, rheumatoid arthritis, sarcoidosis, transplant rejection, vasculitis, interstitial cystitis, or combination thereof.
  • the imidazole and/or thiazole compounds described herein are effective to treat GSK-3 mediated disorders, wherein the GSK-3 mediated disorder is a bone disease chosen from bone spur, bone tumor, craniosynostosis, coffin-lowry syndrome, fibrodysplasia ossifcans progressiva, fibrous dysplasia, fong disease, fracture, giant cell tumor of bone, greenstick fracture, hypophosphatasia, klippel-feil syndrome, metabolic bone diseease, multiple myeloma, nail-patella syndrome, osteoarthritis, osteitis deformans, osteitis fibrosa cystica, osteitis pubis, condensing osteitis, osteochondritis dissecans, osteochondroma, osteogenesis imperfecta, osteomalacia, osteomyelitis, osteopenia, osteopetrosis, osteoporosis, porotic hyperostosis, primary hyperparathyroidism, proteus syndrome, renal osteo
  • the imidazole and/or thiazole compounds described herein are effective to treat GSK-3 mediated disorders, wherein the GSK-3 mediated disorder is a renal disease chosen from parenchymal renal disease, proliferative renal disease, or combination thereof.
  • the imidazole and/or thiazole compounds described herein are effective to treat GSK-3 mediated disorders, wherein the GSK-3 mediated disorder is chosen from Alport Syndrome, amyloidosis and kidney disease, glomerular disease, goodpasture syndrome, horseshoe kidney, IgA nephropathy, lupus nephritis, nephrotic syndrome, nephrotic syndrome in adults, renal dysplasia and cystic disease, renal tubular acidosis, renovascular disease, solitary kidney, or combination thereof.
  • the GSK-3 mediated disorder is chosen from Alport Syndrome, amyloidosis and kidney disease, glomerular disease, goodpasture syndrome, horseshoe kidney, IgA nephropathy, lupus nephritis, nephrotic syndrome, nephrotic syndrome in adults, renal dysplasia and cystic disease, renal tubular acidosis, renovascular disease, solitary kidney, or combination thereof.
  • the imidazole and/or thiazole compounds described herein are effective to treat GSK-3 mediated disorders, wherein the GSK-3 mediated disorder is an HIV-related neurological disorder chosen from dementia, viral infections, fungal and parasitic infections, neuropathy, vacuolar myelopathy, psychological conditions, lymphomas, neurosyphilis, or combination thereof.
  • the imidazole and/or thiazole compounds described herein are effective to treat GSK-3 mediated disorders, wherein the GSK-3 mediated disorder is neuroAIDS.
  • the imidazole and/or thiazole compounds described herein are effective to treat GSK-3 mediated disorders, wherein the GSK-3 mediated disorder is a CNS disease chosen from mood disorders, bipolar disorders, cognitive impairments, schizophrenia, depression, catalepsy, epilepsy, encephalitis, meningitis, migraine, topical spastic paraparesis, arachnoiod cysts, Huntington's Disease, Alzheimer's Disease, attention deficit/hyperactivity disorder (i.e., ADHD), Locked-in Syndrome, Parkinson's Disease, Tourett's, multiple sclerosis, or combination thereof.
  • a CNS disease chosen from mood disorders, bipolar disorders, cognitive impairments, schizophrenia, depression, catalepsy, epilepsy, encephalitis, meningitis, migraine, topical spastic paraparesis, arachnoiod cysts, Huntington's Disease, Alzheimer's Disease, attention deficit/hyperactivity disorder (i.e., ADHD), Locked-in Syndrome, Parkinson's Disease
  • the methods for treating GSK-3 mediated disorders include systemic administration of the imidazole and/or thiazole compounds, or pharmaceutically-acceptable salts or solvates thereof.
  • the systemic administration of the imidazole and/or thiazole compounds may be selected from the group consisting of oral, sublingual, subcutaneous, intravenous, intramuscular, intranasal, intrathecal, intraperitoneal, percutaneous, intranasal, and enteral administration, and combinations thereof.
  • the systemic administration of the imidazole and/or thiazole compounds is oral.
  • the methods for treating GSK-3 mediated disorders include administration of at least one imidazole and/or thiazole compound, or pharmaceutically-acceptable salts or solvates thereof, to a subject in need thereof in a dose of from about 0.1 mg/kg to about 20 mg/kg, or from about 0.3 mg/kg to about 15 mg/kg, or from about 1 mg/kg to about 10 mg/kg, or from about 3 mg/kg to about 10 mg/kg, or from about 5 mg/kg to about 10 mg/kg. It is contemplated that such doses serve as non-limiting examples of suitable doses of imidazole and/or thiazole compounds for a subject in need thereof.
  • At least one imidazole and/or thiazole compound is administered to a subject in need thereof in a dose of about 1 mg/kg. In further embodiments, the dose of imidazole and/or thiazole compounds is administered daily. In still further embodiments, the dose of imidazole and/or thiazole compounds is administered at least once a day.
  • the dose of imidazole and/or thiazole compounds is administered more often than one time a day; for example, the dose of imidazole and/or thiazole compounds is administered at least two times a day, at least three times a day, at least four times a day, at least five times a day, and/or at least six times a day.
  • the methods for treating the GSK-3 mediated disorder include administration of at least one imidazole and/or thiazole compound, or pharmaceutically-acceptable salts or solvates thereof, to a subject in need thereof, wherein the subject is a mammal.
  • the subject is a mammal chosen from humans, non-human primates, canines, felines, murines, bovines, equines, porcines, and lagomorphs.
  • the methods for treating GSK-3 mediated disorder in a subject in need thereof further include monitoring disease development and/or progression and repeating administration of imidazole and/or thiazole compounds (or pharmaceutically-acceptable salts or solvates thereof) one or more times, thereby treating the GSK-3 mediated disorder.
  • Development and/or progression of the GSK-3 mediated disorder can be monitored in a variety of ways known to the skilled clinician.
  • a clinician may administer an additional dose of at least one imidazole and/or thiazole compound. The clinician may then reassess disease development and/or progression. Successive rounds of administering imidazole and/or thiazole compounds coupled with monitoring development and/or progression of the GSK-3 mediated disorder, may be necessary in order to achieve the desired treatment of the GSK-3 mediated disorder.
  • Embodiments of the methods for treating a GSK-3 mediated disorder have been described in detail. Further embodiments of pharmaceutical compositions for modulation, such as, e.g., inhibition, of GSK-3 activity, modulation of GSK-3 signaling, and/or treatment of GSK-3 mediated disorders and/or diseases will now be described.
  • compositions for Modulation of GSK-3 Activity Modulation of GSK-3 Signaling and/or Treatment of GSK-3 Mediated Disorders
  • compositions for the modulation such as, e.g., inhibition, of GSK-3 activity, modulation of GSK-3 signaling, and/or treatment of GSK-3 mediated disorders and/or diseases are disclosed herein and may be employed in the methods previously described.
  • a pharmaceutical composition including at least one imidazole and/or thiazole compound, or a pharmaceutically-acceptable salt or solvate thereof, as an active agent (i.e., an active ingredient) is disclosed.
  • a pharmaceutical composition including the imidazole and/or thiazole compounds as an active agent is disclosed, wherein the imidazole and/or thiazole compound is formulated for administration to a subject for the inhibition of GSK-3 activity, modulation of GSK-3 signaling, and/or treatment of GSK-3 mediated disorders.
  • the imidazole and/or thiazole compounds referenced herein are as previously described.
  • the pharmaceutical composition includes a therapeutically effective amount of one or more imidazole and/or thiazole compounds.
  • the provided pharmaceutical compositions do not contain any of the compounds listed in TABLE 2. In some embodiments, the provided pharmaceutical compositions include one or more compounds listed in TABLE 2. In some embodiments, the provided pharmaceutical compositions include one or more compounds listed in TABLE 2 in combination with one or more compounds listed in TABLE 1.
  • the pharmaceutical composition for the modualtion such as, e.g., inhibition, of GSK-3 activity, modulation of GSK-3 signaling, and/or treatment of GSK-3 mediated disorders and/or diseases further includes an additional active agent.
  • the pharmaceutical composition for the modulation such as, e.g., the inhibition, of GSK-3 activity, modulation of GSK-3 signaling, and/or treatment of GSK-3 mediated disorders and/or diseases further includes a therapeutically effective amount of an additional active agent for the treatment of conditions associated with modulation, such as, e.g., inhibition, of GSK-3 activity, modulation of GSK-3 signaling, and/or treatment of GSK-3 mediated disorders and/or diseases.
  • the pharmaceutical composition may further include an additional active agent for the treatment of leukemia, pancreatic cancer, multiple myeloma, glioblastoma, Parkinson's Disease, Alzheimer's Disease, ALS, atherosclerosis, cardiac ischemia, cardiac reperfusion injury, cardiac hypertrophy, sepsis, toxic shock, parenchymal renal disease, proliferative renal disease, neuroAIDS, bipolar disorder, mood disorder, schizophrenia, depression, or combination thereof.
  • the pharmaceutical composition for the modulation such as, e.g., inhibition, of GSK-3 activity, modulation of GSK-3 signaling, and/or treatment of GSK-3 mediated disorders and/or diseases further includes a pharmaceutically acceptable carrier and/or excipient.
  • suitable pharmaceutically acceptable carriers may include a wide range of known diluents (i.e., solvents), fillers, extending agents, adjuvants, binders, suspending agents, disintegrates, surfactants, lubricants, wetting agents, preservatives, stabilizers, antioxidants, antimicrobials, buffering agents and the like commonly used in this field. Such carriers may be used singly or in combination according to the form of the pharmaceutical preparation.
  • a preparation resulting from the inclusion of a pharmaceutically acceptable carrier may incorporate, if necessary, one or more solubilizing agents, buffers, preservatives, colorants, perfumes, flavorings and the like, as widely used in the field of pharmaceutical preparation.
  • excipients examples include water, saline, Ringer's solution, dextrose solution, and solutions of ethanol, glucose, sucrose, dextran, mannose, mannitol, sorbitol, polyethylene glycol (i.e., PEG), phosphate, acetate, gelatin, collagen, Carbopol®, and vegetable oils.
  • PEG polyethylene glycol
  • Suitable adjuvants include inorganic compounds (e.g., aluminum hydroxide, aluminum phosphate, calcium phosphate hydroxide, and beryllium), mineral oil (e.g., paraffin oil), bacterial products (e.g., killed bacteria Bordetelle pertussis, Mycobacterium bovis , and toxoids), nonbacterial organics (e.g., squalene and thimerosal), delivery systems (e.g., detergents (Quil A)), cytokines (e.g., IL-1, IL-2, and IL-12), and combinations (e.g., Freund's complete adjuvant, Freund's incomplete adjuvant).
  • inorganic compounds e.g., aluminum hydroxide, aluminum phosphate, calcium phosphate hydroxide, and beryllium
  • mineral oil e.g., paraffin oil
  • bacterial products e.g., killed bacteria Bordetelle pertussis, Mycobacterium bovis , and toxoids
  • suitable preservatives, stabilizers, antioxidants, antimicrobials, and buffering agents include BHA, BHT, citric acid, ascorbic acid, tetracycline, and the like.
  • Cream or ointment bases useful in formulation include lanolin, Silvadene® (Marion), Aquaphor® (Duke Laboratories).
  • the pharmaceutical composition for modulation such as, e.g., inhibition, of GSK-3 activity, modulation of GSK-3 signaling, and/or treatment of GSK-3 mediated disorders and/or diseases includes at least one imidazole and/or thiazole compound, or a pharmaceutically-acceptable salt or solvate thereof, formulated into a dosage form.
  • at least one imidazole and/or thiazole compound is formulated into a dosage form selected from the group consisting of creams, emulsions, ointments, gels, tablets, capsules, granules, pills, injections, solutions, suspensions, and syrups.
  • the form and administration route for such pharmaceutical composition are not limited and can be suitably selected.
  • tablets, capsules, granules, pills, syrups, solutions, emulsions, and suspensions may be administered orally.
  • injections e.g., subcutaneous, intravenous, intramuscular, and intraperitoneal
  • injections may be administered intravenously either singly or in combination with a conventional replenisher containing glucose, amino acid and/or the like, or may be singly administered intramuscularly, intracutaneously, subcutaneously and/or intraperitoneally.
  • a pharmaceutical composition for the modulation such as, e.g., inhibition, of GSK-3 activity, modulation of GSK-3 signaling, and/or treatment of GSK-3 mediated disorders and/or diseases may be prepared according to methods known in the pharmaceutical field using a pharmaceutically acceptable carrier.
  • oral forms such as tablets, capsules, granules, pills and the like are prepared according to known methods using excipients such as saccharose, lactose, glucose, starch, mannitol and the like; binders such as syrup, gum arabic, sorbitol, tragacanth, methylcellulose, polyvinylpyrrolidone and the like; disintegrates such as starch, carboxymethylcellulose or the calcium salt thereof, microcrystalline cellulose, polyethylene glycol and the like; lubricants such as talc, magnesium stearate, calcium stearate, silica and the like; and wetting agents such as sodium laurate, glycerol and the like.
  • excipients such as saccharose, lactose, glucose, starch, mannitol and the like
  • binders such as syrup, gum arabic, sorbitol, tragacanth, methylcellulose, polyvinylpyrrolidone and the like
  • disintegrates such as starch,
  • Injections, solutions, emulsions, suspensions, syrups and the like may be prepared according to known methods suitably using solvents for dissolving the active agent, such as ethyl alcohol, isopropyl alcohol, propylene glycol, 1,3-butylene glycol, polyethylene glycol, sesame oil and the like; surfactants such as sorbitan fatty acid ester, polyoxyethylenesorbitan fatty acid ester, polyoxyethylene fatty acid ester, polyoxyethylene of hydrogenated castor oil, lecithin and the like; suspending agents such as cellulose derivatives including carboxymethylcellulose sodium, methylcellulose and the like, natural gums including tragacanth, gum arabic and the like; and preservatives such as parahydroxybenzoic acid esters, benzalkonium chloride, sorbic acid salts and the like.
  • solvents for dissolving the active agent such as ethyl alcohol, isopropyl alcohol, propylene glycol, 1,3-butylene glycol,
  • the pharmaceutical composition for the modulation such as, e.g., inhibition, of GSK-3 activity, modulation of GSK-3 signaling, and/or treatment of GSK-3 mediated disorders and/or diseases is provided for administration to a subject in unit dose and/or multi-dose containers, e.g., vials and/or ampoules.
  • the pharmaceutical composition for the modulation such as, e.g., inhibition, of GSK-3 activity, modulation of GSK-3 signaling, and/or treatment of GSK-3 mediated disorders and/or diseases is provided for administration to a subject in a device including a reservoir.
  • the pharmaceutical composition for the modulation such as, e.g., inhibition, of GSK-3 activity, modulation of GSK-3 signaling, and/or treatment of GSK-3 mediated disorders and/or diseases is provided for administration to a subject in a device including a reservoir which is a vial, wherein the device is a syringe.
  • compositions for the modulation such as, e.g., inhibition of GSK-3 activity, modulation of GSK-3 signaling, and/or treatment of GSK-3 mediated disorders and/or diseases as described herein may be contacted with a cell expressing GSK-3 and/or may be administered to a subject in need thereof, as described previously.
  • compositions for modulation such as, e.g., inhibition, of GSK-3 activity, modulation of GSK-3 signaling, and/or treatment of GSK-3 mediated disorders and/or diseases have been described in detail.
  • the imidazole and/or thiazole compound, or a pharmaceutically-acceptable salt or solvate thereof are incorporated into a pharmaceutical composition for the inhibition of GSK-3 activity, modulation of GSK-3 signaling, and/or treatment of GSK-3 mediated disorders and/or diseases and/or are formulated into a dosage form for the inhibition of GSK-3 activity, modulation of GSK-3 signaling, and/or treatment of GSK-3 mediated disorders and/or diseases, as previously described.
  • the imidazole and/or thiazole compounds referenced herein are as previously described.
  • Methods according to embodiments herein may find use in probing the molecular mechanisms of normal and abnormal cellular processes. Methods according to embodiments herein may find use in probing the molecular mechanisms of normal physiology and pathology. Methods according to embodiments herein may be used to engender normal physiology. Methods according to embodiments herein may be used to kill or diminish the presence of microbes. Methods according to embodiments herein may be used to aid the processing of valuable products from biological sources. Methods according to embodiments herein may be a component of a diagnostic or prognostic assay.
  • a method for modulating glycogen synthase kinase-3 (GSK-3) activity in a cell expressing GSK-3 includes contacting the cell with a therapeutically effective amount of at least one compound of General Formula (I) or (II):
  • a method according to the first aspect is disclosed, wherein the contacting is effective to modulate the activity of at least one of GSK-3 ⁇ or GSK-3 ⁇ in the cell.
  • a method according to the first or the second aspect wherein the activity of GSK-3 is modulated by inhibiting the activity thereof.
  • a method according to the first to the third aspects wherein the activity of GSK-3 is modulated by inhibiting the activity thereof by at least about 50%.
  • a method according to the first to the fourth aspects wherein the activity of GSK-3 is modulated by inhibiting the activity thereof by at least about 75%.
  • a method according to the first to the fifth aspects wherein the at least one compound of General Formula (I) or (II) is provided in a concentration of from about 1 nM to about 50 M.
  • a method according to the first to the sixth aspects wherein the activity of GSK-3 is modulated by inhibiting the activity thereof, and wherein at least one compound of General Formula (I) or (II) has an IC 50 value of from about 100 pM to about 50 M.
  • a method according to the first to the eighth aspects is disclosed, wherein the contacting is effective to modulate signaling of GSK-3.
  • a method according to the first to the ninth aspects is disclosed, wherein the contacting is effective to enhance expression of ⁇ -catenin.
  • a method according to the first to the eleventh aspects wherein the contacting is effective to suppress expression of at least one of i-Nitrous-Oxide Synthase (iNOS), Interleukin-6 (IL-6), Tumor Necrosis Factor- ⁇ (TNF- ⁇ ), Interleukin 1 ⁇ (IL-1 ⁇ ), Interleukin 1 ⁇ (IL-1 ⁇ ), Interferon ⁇ (IFN- ⁇ ), or Interferon ⁇ (IFN- ⁇ ).
  • iNOS i-Nitrous-Oxide Synthase
  • IL-6 Interleukin-6
  • TNF- ⁇ Tumor Necrosis Factor- ⁇
  • IL-1 ⁇ Interleukin 1 ⁇
  • IL-1 ⁇ Interleukin 1 ⁇
  • IFN- ⁇ Interferon ⁇
  • IFN- ⁇ Interferon ⁇
  • a method according to the first to the twelfth aspects is disclosed, wherein the contacting is effected in vitro.
  • a method according to the first to the twelfth aspects is disclosed, wherein the contacting is effected in vivo.
  • a method according to the first to the fourteenth aspects is disclosed, wherein the activity of GSK-3 is a phosphorylation activity.
  • a method according to the first to the fifteenth aspects is disclosed, wherein the cell is a mammalian cell.
  • a method according to the first to the sixteenth aspects wherein the at least one compound of General Formula (I) or (II) is a thiazole 2-thione.
  • a method according to the first to the seventeenth aspects wherein: R 3 is —H; X is S; and Y is S in the at least one compound of General Formula (I) or (II).
  • R 1 is chosen from C 1 to C 4 aliphatic or heteroaliphatic groups optionally substituted with one or more aryl groups, substituted aryl groups, heteroaryl groups, substituted heteroaryl groups, or combination thereof;
  • R 3 is —H;
  • X is S; and
  • Y is S in the at least one compound of General Formula (I) or (II).
  • a method according to the first to the nineteenth aspects is disclosed, wherein R 2 is chosen from unsubstituted phenyl groups, substituted phenyl groups, or heteroaryl groups in which one or more ring atoms is N; R 3 is —H; X is S; and Y is S in the at least one compound of General Formula (I) or (II).
  • R 1 is chosen from C 1 to C 4 aliphatic groups optionally substituted with heteroaryl groups in which one or more ring atoms is N, or combination thereof;
  • R 2 is chosen from unsubstituted phenyl groups, substituted phenyl groups, or heteroaryl groups in which one or more ring atoms is N;
  • R 3 is —H;
  • X is S; and
  • Y is S in the at least one compound of General Formula (I) or (II).
  • R 1 is chosen from methyl, ethyl, propyl, butyl, 2-propenyl,
  • a method according to the first to the twenty-third aspects wherein the at least one compound of General Formula (I) or (II) is chosen from COB-152, COB-187, COB-188, COB-198, COB-222, COB-223, COB-224, COB-225, COB-226, or combination thereof, and pharmaceutically acceptable salts and solvates thereof:
  • a method for modulating glycogen synthase kinase-3 (GSK-3) signaling includes contacting a cell expressing GSK-3 with a therapeutically effective amount of at least one compound of General Formula (I) or (II):
  • R 1 is chosen from C 1 to C 10 aliphatic or heteroaliphatic groups, optionally substituted with one or more aryl groups, substituted aryl groups, heteroaryl groups, substituted heteroaryl groups, or combination thereof;
  • R 2 is chosen from aryl groups, substituted aryl groups, heteroaryl groups, substituted heteroaryl groups, and coumarin;
  • R 3 is chosen from —H, C 1 to C 10 aliphatic or heteroaliphatic groups, phenyl, or substituted phenyl, wherein the aliphatic or heteroaliphatic groups are optionally substituted with one or more phenyl groups, aryl groups, heteroaryl groups, substituted heteroaryl groups, or combination thereof;
  • X is S or O; and
  • Y is S or NH; with the proviso that when R 2 is phenyl and R 3 is —H, at least one of the following is true: (a) R 1 is a C 1 to C
  • a method according to the twenty-fifth aspect is disclosed, wherein the contacting is effective to modulate signaling of GSK-3, resulting in at least one of enhanced expression of ⁇ -catenin, inhibited function of lipopolysaccharide (LPS), or suppressed expression of i-Nitrous-Oxide Synthase (iNOS), Interleukin-6 (IL-6), Tumor Necrosis Factor- ⁇ (TNF- ⁇ ), Interleukin 1 ⁇ (IL-1 ⁇ ), Interleukin 1 ⁇ (IL-1 ⁇ ), Interferon ⁇ (IFN- ⁇ ), and/or Interferon ⁇ (IFN- ⁇ ).
  • IL-6 Interleukin-6
  • TNF- ⁇ Tumor Necrosis Factor- ⁇
  • IL-1 ⁇ Interleukin 1 ⁇
  • IL-1 ⁇ Interleukin 1 ⁇
  • IFN- ⁇ Interferon ⁇
  • IFN- ⁇ Interferon ⁇
  • a method according to the twenty-fifth or the twenty-sixth aspect is disclosed, wherein the at least one compound of General Formula (I) or (II) is a thiazole 2-thione.
  • a method according to the twenty-fifth to the twenty-seventh aspects is disclosed, wherein: R 3 is —H; X is S; and Y is S in the at least one compound of General Formula (I) or (II).
  • R 1 is chosen from C 1 to C 4 aliphatic or heteroaliphatic groups optionally substituted with one or more aryl groups, substituted aryl groups, heteroaryl groups, substituted heteroaryl groups, or combination thereof;
  • R 3 is —H;
  • X is S; and
  • Y is S in the at least one compound of General Formula (I) or (II).
  • a method according to the twenty-fifth to the twenty-ninth aspects is disclosed, wherein R 2 is chosen from unsubstituted phenyl groups, substituted phenyl groups, or heteroaryl groups in which one or more ring atoms is N; R 3 is —H; X is S; and Y is S in the at least one compound of General Formula (I) or (II).
  • R 1 is chosen from C 1 to C 4 aliphatic or heteroaliphatic groups optionally substituted with one or more aryl groups, substituted aryl groups, heteroaryl groups, substituted heteroaryl groups, or combination thereof;
  • R 2 is chosen from unsubstituted phenyl groups, substituted phenyl groups, or heteroaryl groups in which one or more ring atoms is N;
  • R 3 is —H;
  • X is S; and Y is S in the at least one compound of General Formula (I) or (II).
  • a method according to the twenty-fifth to the thirty-first aspects wherein R 1 is chosen from C 1 to C 4 aliphatic groups optionally substituted with heteroaryl groups in which one or more ring atoms is N, or combination thereof; R 2 is chosen from unsubstituted phenyl groups, substituted phenyl groups, or heteroaryl groups in which one or more ring atoms is N; R 3 is —H; X is S; and Y is S in the at least one compound of General Formula (I) or (II).
  • a method according to the twenty-fifth to the thirty-first aspects is disclosed, wherein R 1 is chosen from methyl, ethyl, propyl, butyl, 2-propenyl,
  • a method according to the twenty-fifth to the thirty-third aspects wherein the at least one compound of General Formula (I) or (II) is chosen from COB-152, COB-187, COB-188, COB-198, COB-222, COB-223, COB-224, COB-225, COB-226, or combination thereof, and pharmaceutically acceptable salts and solvates thereof:
  • a method for treating a GSK-3-mediated disorder in a subject in need thereof includes: administering to the subject a therapeutically effective amount of at least one compound of General Formula (I) or (II):
  • R 1 is chosen from C 1 to C 10 aliphatic or heteroaliphatic groups, optionally substituted with one or more aryl groups, substituted aryl groups, heteroaryl groups, substituted heteroaryl groups, or combination thereof;
  • R 2 is chosen from aryl groups, substituted aryl groups, heteroaryl groups, substituted heteroaryl groups, and coumarin;
  • R 3 is chosen from —H, C 1 to C 10 aliphatic or heteroaliphatic groups, phenyl, or substituted phenyl, wherein the aliphatic or heteroaliphatic groups are optionally substituted with one or more phenyl groups, aryl groups, heteroaryl groups, substituted heteroaryl groups, or combination thereof;
  • X is S or O; and
  • Y is S or NH; with the proviso that when R 2 is phenyl and R 3 is —H, at least one of the following is true: (a) R 1 is a C 1 to C
  • a method according to the thirty-fifth aspect is disclosed, wherein the GSK-3 mediated disorder is chosen from malaria, cancer, insulin resistance, type 2 diabetes mellitus, muscle wasting, neurodegenerative disease, cardiovascular disease, myocardial disease, pathological inflammation, bone disease, renal disease, human immunodeficiency virus (HIV)-related neurological disorder, sepsis, toxic shock, psychiatric disease, central nervous system (CNS) disease, or combination thereof.
  • the GSK-3 mediated disorder is chosen from malaria, cancer, insulin resistance, type 2 diabetes mellitus, muscle wasting, neurodegenerative disease, cardiovascular disease, myocardial disease, pathological inflammation, bone disease, renal disease, human immunodeficiency virus (HIV)-related neurological disorder, sepsis, toxic shock, psychiatric disease, central nervous system (CNS) disease, or combination thereof.
  • HIV human immunodeficiency virus
  • a method according to the thirty-fifth or the thirty-sixth aspect is disclosed, wherein the GSK-3 mediated disorder is chosen from leukemia, pancreatic cancer, multiple myeloma, glioblastoma, or combination thereof.
  • a method according to the thirty-fifth or the thirty-sixth aspect is disclosed, wherein the GKS-3 mediated disorder is acute lymphoblastic leukemia (ALL).
  • ALL acute lymphoblastic leukemia
  • a method according to thirty-fifth or the thirty-sixth aspect is disclosed, wherein the GSK-3 mediated disorder is chosen from Parkinson's Disease, Alzheimer's Disease, amyotrophic lateral sclerosis (ALS), or combination thereof.
  • the GSK-3 mediated disorder is chosen from Parkinson's Disease, Alzheimer's Disease, amyotrophic lateral sclerosis (ALS), or combination thereof.
  • a method according to thirty-fifth or the thirty-sixth aspect wherein the GSK-3 mediated disorder is chosen from atherosclerosis, cardiac ischemia, cardiac reperfusion injury, cardiac hypertrophy, or combination thereof.
  • a method according to thirty-fifth or the thirty-sixth aspect is disclosed, wherein the GSK-3 mediated disorder is chosen from sepsis, toxic shock, or combination thereof.
  • a method according to the thirty-fifth or the thirty-sixth aspect is disclosed, wherein the GSK-3 mediated disorder is chosen from parenchymal renal disease, proliferative renal disease, or combination thereof.
  • a method according to the thirty-fifth or the thirty-sixth aspect is disclosed, wherein the GSK-3 mediated disorder is neuroAIDS.
  • a method according to the thirty-fifth or the thirty-sixth aspect is disclosed, wherein the GSK-3 mediated disorder is chosen from bipolar disorder, mood disorder, schizophrenia, depression, or combination thereof.
  • a method according to the thirty-fifth to the forty-sixth aspects is disclosed, wherein the at least one compound of General Formula (I) or (II) is a thiazole 2-thione.
  • a method according to the thirty-fifth to the forty-fifth aspects is disclosed, wherein: R 3 is —H; X is S; and Y is S in the at least one compound of General Formula (I) or (II).
  • a method according to the thirty-fifth to the forty-sixth aspects is disclosed, wherein R 1 is chosen from C 1 to C 4 aliphatic or heteroaliphatic groups optionally substituted with one or more aryl groups, substituted aryl groups, heteroaryl groups, substituted heteroaryl groups, or combination thereof; R 3 is —H; X is S; and Y is S in the at least one compound of General Formula (I) or (II).
  • a method according to the thirty-fifth to the forty-seventh aspects wherein R 2 is chosen from unsubstituted phenyl groups, substituted phenyl groups, or heteroaryl groups in which one or more ring atoms is N; R 3 is —H; X is S; and Y is S in the at least one compound of General Formula (I) or (II).
  • R 1 is chosen from C 1 to C 4 aliphatic or heteroaliphatic groups optionally substituted with one or more aryl groups, substituted aryl groups, heteroaryl groups, substituted heteroaryl groups, or combination thereof;
  • R 2 is chosen from unsubstituted phenyl groups, substituted phenyl groups, or heteroaryl groups in which one or more ring atoms is N;
  • R 3 is —H;
  • R 1 is chosen from C 1 to C 4 aliphatic groups optionally substituted with heteroaryl groups in which one or more ring atoms is N, or combination thereof;
  • R 2 is chosen from unsubstituted phenyl groups, substituted phenyl groups, or heteroaryl groups in which one or more ring atoms is N;
  • R 3 is —H;
  • X is S; and
  • Y is S in the at least one compound of General Formula (I) or (II).
  • a method according to the thirty-fifth to the forty-ninth aspects is disclosed, wherein R 1 is chosen from methyl, ethyl, propyl, butyl, 2-propenyl,
  • a method according to the thirty-fifth to the fifty-first aspects wherein the at least one compound of General Formula (I) or (II) is chosen from COB-152, COB-187, COB-188, COB-198, COB-222, COB-223, COB-224, COB-225, COB-226, or combination thereof, and pharmaceutically acceptable salts and solvates thereof:
  • a method according to the thirty-fifth to the fifty-second aspects is disclosed, wherein the administering includes administering a pharmaceutical composition including the at least one compound of General Formula (I) or (II) in combination with at least one pharmaceutically-acceptable carrier.
  • a method for modulating glycogen synthase kinase-3 (GSK-3) activity in a cell expressing GSK-3 including: contacting the cell with a therapeutically effective amount of at least one compound of General Formula (II):
  • R 1 is chosen from C 1 to C 10 aliphatic or heteroaliphatic groups, optionally substituted with one or more aryl groups, substituted aryl groups, heteroaryl groups, substituted heteroaryl groups, or combination thereof;
  • R 2 is chosen from aryl groups, substituted aryl groups, heteroaryl groups, substituted heteroaryl groups, and coumarin;
  • R 3 is chosen from —H, C 1 to C 10 aliphatic or heteroaliphatic groups, phenyl, or substituted phenyl, wherein the aliphatic or heteroaliphatic groups are optionally substituted with one or more phenyl groups, aryl groups, heteroaryl groups, substituted heteroaryl groups, or combination thereof;
  • X is S or O; and
  • Y is S or NH; with the proviso that when R 2 is phenyl and R 3 is —H, at least one of the following is true: (a) R 1 is a C 1 to C
  • a method according to the fifty-fourth aspect wherein the at least one compound of General Formula (II) is chosen from COB-152, COB-187, COB-188, COB-198, COB-222, COB-223, COB-224, COB-225, COB-226, or combination thereof, and pharmaceutically acceptable salts and solvates thereof:
  • a method for inhibiting glycogen synthase kinase-3 (GSK-3) activity in a cell expressing GSK-3 including: contacting the cell with a therapeutically effective amount of at least one compound of General Formula (II):
  • R 1 is chosen from C 1 to C 10 aliphatic or heteroaliphatic groups, optionally substituted with one or more aryl groups, substituted aryl groups, heteroaryl groups, substituted heteroaryl groups, or combination thereof;
  • R 2 is chosen from aryl groups, substituted aryl groups, heteroaryl groups, substituted heteroaryl groups, and coumarin;
  • R 3 is chosen from —H, C 1 to C 10 aliphatic or heteroaliphatic groups, phenyl, or substituted phenyl, wherein the aliphatic or heteroaliphatic groups are optionally substituted with one or more phenyl groups, aryl groups, heteroaryl groups, substituted heteroaryl groups, or combination thereof;
  • X is S or O; and
  • Y is S or NH; with the proviso that when R 2 is phenyl and R 3 is —H, at least one of the following is true: (a) R 1 is a C 1 to C
  • a method according to the fifty-sixth aspect wherein the at least one compound of General Formula (II) is chosen from COB-152, COB-187, COB-188, COB-198, COB-222, COB-223, COB-224, COB-225, COB-226, or combination thereof, and pharmaceutically acceptable salts and solvates thereof:
  • X ⁇ S; Y ⁇ S; and R 1 and R 2 may be synthesized by adding carbon disulfide (CS 2 ; 150 mol. %) and K 2 CO 3 (50 mol. %) to a solution of an amine of the formula (2a):
  • reaction mixture (100 mol %) to form a reaction mixture.
  • the reaction mixture is stirred in an open flask at room temperature (25° C. ⁇ 2° C.) for 1 hour to 3 hours.
  • the crude reaction mixture is extracted with ethyl acetate (EtOAc; 3 ⁇ 10 mL), and the combined organic layers are dried over MgSO 4 and filtered.
  • the solvent is evaporated by rotary evaporation.
  • the product is isolated by flash chromatography using 10%-20% EtOAc in hexanes. In some cases, some products may precipitate during the reaction. In such cases the product may be isolated by filtration, washed thoroughly with solvent (EtOH:H 2 O, 1:1), then dried.
  • Compounds having General Formula (I), in which X ⁇ O or S; Y ⁇ S; and R 1 and R 2 are as described above, may be synthesized by dehydrating a compound having General Formula (II) prepared according to Synthetic Example 2 or by any other suitable method, in which groups R 1 , R 2 , X, and Y of the compound having General Formula (II) are the same as those in the desired compound having General Formula (I).
  • COB-176 was prepared according to Synthetic Example 2 on a 1.5-mmol scale. Based on 104 mg of product recovered, the yield was 23%.
  • COB-180 was prepared according to Synthetic Example 2 on a 1.88-mmol scale. Based on 300 mg of product recovered, the yield was 84%.
  • R f 0.34 (20% EtOAc in hexanes); t R 10.8 min;
  • COB-189 was prepared from COB-180 according to Synthetic Example 3 on a 0.5-mmol scale. Based on 129.4 mg of product recovered, the yield was 91%.
  • R f 0.16 (20% EtOAc in hexanes); t R 6.05 min; 1 H NMR (CDCl 3 , 300 MHz) ⁇ 8.460-8.39 (m, 1H, Ar), 7.56-7.50 (m, 1H, Ar), 7.35-6.98 (m, 7H, Ar), 6.47 (s, 1H, CH), 5.37 (s, 2H, NCH 2 ); 13 C NMR (CDCl 3 , 75 MHz) ⁇ 189.2, 155.0, 149.7, 145.4, 136.7, 130.8, 130.1, 129.6, 129.0, 122.5, 121.7, 52.8.
  • COB-183 was prepared according to Synthetic Example 2 on a 1.88-mmol scale. Based on 214 mg of product recovered, the yield was 50%.
  • COB-192 was prepared from COB-183 according to Synthetic Example 3 on a 0.07-mmol scale. Based on 13 mg of product recovered, the yield was 63%.
  • R f 0.4 5% EtOAc in toluene
  • t R 6.95 min
  • COB-187 was prepared according to Synthetic Example 2 on a 1.88-mmol scale. Based on 70 mg of product recovered, the yield was 20%.
  • R f 0.3 (10% EtOAc in toluene); t R 8.59 min;
  • COB-203 was prepared from COB-197 according to Synthetic Example 3 on a 0.27-mmol scale. Based on 84 mg of product recovered, the yield was 90%.
  • COB-198 was prepared according to Synthetic Example 2 on a 1.5-mmol scale. Based on 69.9 mg of product recovered, the yield was 22%.
  • COB-204 was prepared from COB-199 according to Synthetic Example 3 on a 0.28-mmol scale. Based on 81 mg of product recovered, the yield was 87%.
  • COB-200 was prepared according to Synthetic Example 2 on a 1.5-mmol scale. Based on 131 mg of product recovered, the yield was 40%.
  • COB-201 was prepared according to Synthetic Example 2 on a 1.6-mmol scale. Based on 153 mg of product recovered, the yield was 46%.
  • COB-205 was prepared from COB-202 according to Synthetic Example 3 on a 0.13-mmol scale. Based on 33.4 mg of product recovered, the yield was 70%.
  • R f 0.25 (60% EtOAc in hexanes); t R 3.46 min (LCMS); 1 H NMR (CDCl 3 , 300 MHz) ⁇ 8.34 (s, 1H, Ar), 8.20 (s, 1H, Ar), 7.59-7.43 (m, 2H, Ar), 7.34 (s, 1H, Ar), 7.33-7.30 (m, 2H, Ar), 7.25-7.06 (m, 1H, Ar), 6.59 (s, 1H, CH), 5.51 (s, 2H, CH 2 ).
  • COB-222 may be prepared according to Synthetic Example 2.
  • COB-223 may be prepared according to Synthetic Example 2.
  • COB-224 may be prepared according to Synthetic Example 2.
  • COB-225 may be prepared according to Synthetic Example 2.
  • COB-226 may be prepared according to Synthetic Example 2.
  • the compounds COB-152 and COB-187 were mixed with GSK-3 ⁇ or GSK-3 ⁇ in the presence of a Ser/Thr substrate and ATP.
  • the level of compound was varied, and the reaction was carried out for 60 minutes at room temperature. Subsequently, the solution was developed and the fluorescence was read to infer the activity of the protein.
  • FIGS. 1A, 1B, 2A, and 2B COB-152 and COB-187 inhibit the activity of GSK-3 ⁇ / ⁇ .
  • FIG. 1A shows the effect of COB-152 on GSK-3 ⁇ activity
  • FIG. 1B shows the effect of COB-152 on GSK-3 ⁇ activity
  • FIG. 2A shows the effect of COB-187 on GSK-3 ⁇ activity
  • FIG. 2B shows the effect of COB-187 on GSK-3 ⁇ activity.
  • the IC 50 for each compound was in the nanomolar range.
  • the imidazole and/or thiazole compounds (i.e., I-GSK-3s) had limited effect on non-GSK-3 kinases in a molecular assay.
  • an extensive kinase screen was employed, in which COB-152 was screened against 315 additional kinases at a 2 ⁇ M concentration and COB-187 was screened against select kinases at a 1 ⁇ M concentration.
  • Micro BCA Protein Assay kit was obtained from Thermo Scientific (Rockford, Ill.). Nu-PAGE 4 to 12% Bis-Tris denaturing gels, nitrocellulose membrane (0.2 m), running and transfer buffers, sample reducing agent, loading buffer, and antioxidant were purchased from Invitrogen (Carlsbad, Calif.). Bovine Serum Albumin (i.e., BSA) and 10 ⁇ PBS were obtained from Sigma Aldrich and Gibco, respectively. IRDye (680/800) protein marker, IRDye 800 CW conjugated secondary donkey anti-goat IgG and IRDye 680 CW conjugated donkey anti-rabbit IgG, and stripping buffer were purchased from LI-COR Biosciences (Lincoln, Nebr.). Rabbit monoclonal anti-human total GSK-3 and rabbit polyclonal anti-human ⁇ -catenin antibodies were obtained from Cell Signaling Technology (Danvers, Mass.).
  • RNeasy plus mini kit and Qiashredder columns were obtained from Qiagen (Valencia, Calif.).
  • High capacity cDNA Reverse Transcription Kit, Taqman Gene Expression Master Mix, primer for endogenous control HPRT1 (assay id: HS99999909_m1), and IL-6 primer (assay id: Hs00985639_m1) were obtained from Applied Biosystems (Foster City, Calif.).
  • Mouse ⁇ -catenin (assay id: Mm99999915_g1) and mouse glyceraldehyde 3-phosphate dehydrogenase (i.e., GAPDH) endogenous control (Assay id: Mm99999915_g1) were obtained from Applied Biosystems (Waltham, Mass.).
  • RAW 264.7 cells were cultured in RPMI 1640 medium supplemented with 10% FBS and 0.5% penicillin-streptomycin stabilized solution.
  • THP-1 cells were cultured and differentiated into macrophages using phorbol 12-myristate 13-acetate (i.e., PMA). More specifically, THP-1 cells were cultured in RPMI-1640 10% FBS supplemented with 0.05 mM 2-mercaptoethanol.
  • PMA phorbol 12-myristate 13-acetate
  • THP-1 cells were stimulated with PMA (50 ng/mL) for 24 hours. Differentiated THP-1 cells were washed with fresh media twice before incubation for 24 more hours at 37° C., 5% CO 2 in a humidified incubator.
  • the monolayer was then treated with ox-LDL or native LDL (both at either 50 or 100 ⁇ g/mL) and LPS (10 ng/mL) for 4 hours. Undifferentiated THP-1 cells were cultured and treated under similar conditions were used as a control.
  • GSK-3 inhibition leads to an increased expression of ⁇ -catenin, and this unique property of GSK-3 can be utilized to identify specific GSK-3 inhibitors.
  • RAW 264.7 macrophages and PMA differentiated THP-1 cells were treated with COB-152 or COB 187 at different concentrations or 0.1% (v/v) DMSO solvent for 5 hours. Following treatment, protein was extracted and probed for ⁇ -catenin and total GSK-3 via western blotting.
  • RAW 264.7 cells and PMA differentiated THP-1 cells were treated with varying concentrations of COB-187 or COB-152 dissolved in culture media containing 0.1% (v/v) dimethylsulfoxide (i.e., DMSO) solvent or with 0.1% (v/v) DMSO alone for 5 or 24 hours. After incubation, 20 g protein was extracted from the cells and quantified. More specifically, culture supernatant was collected and store at ⁇ 80° C. until further use.
  • DMSO dimethylsulfoxide
  • the cells were lysed in 10 mM Tris HCl at pH 7.5, 150 mM NaCl, and 1% nonyl phenoxypolyethoxylethanol-40, containing a cocktail of protease inhibitors (Roche, Mannheim, Germany). Insoluble material was pelleted and the supernatant containing total protein as well as the culture supernatant was quantified using a Micro BCA protein kit. 20 g of protein was then resolved onto a denaturing gel, transferred to a nitrocellulose membrane, and immunoblotted with antibodies against GSK-3 and ⁇ -catenin. Signals were detected using the Li-Cor Odyssey Infrared Imaging System (Lincoln, Nebr.). Membranes were stripped and reprobed with primary antibody for ⁇ -actin as a loading control. All experiments were performed at least thrice in both RAW 264.7 and PMA differentiated THP-1 cells, and in duplicates.
  • RAW 264.7 cells were treated with varying concentrations of COB-187, COB-152 or 0.1% (v/v) DMSO solvent alone for 5 or 24 hours.
  • RNA was extracted from the cells and reverse transcribed. More specifically, total RNA was isolated using RNeasy plus mini kit according to the manufacturer's protocol and quantified using a Nanodrop 2000C Spectrophotometer. First-strand cDNA was synthesized from total RNA using cDNA Reverse Transcription Kit according to the manufacturer's protocol. Quantitative RT-PCR was performed using Taqman Gene Expression Assay (Life Technologies, Waltham, Mass.) and mouse primers for GAPDH and ⁇ -catenin. Relative gene expression was determined by normalizing with GAPDH using the comparative Ct method. All experiments were performed at least thrice in duplicates.
  • Human A ⁇ (1-42) peptides were purchased from U.S. Peptide Inc. (Rancho, Cucamonga, Calif.). Primers for quantitative RT-PCR were purchased from Applied Biosystems. Mouse IL-6 primers (Assay id: Mm00446190_m1) and GAPDH endogenous control (Assay id: Mm99999915_g1) were obtained from Applied Biosystems.
  • RAW 264.7 were stimulated with either LPS (10 ng/mL) alone, or in combination with COB-152, COB-187 or 0.1% DMSO solvent for 5 hours. Following incubation, RNA was extracted from the cells. Quantitative RT-PCR was used to quantify expression of mRNA.
  • THP-1 cells were differentiated using PMA (50 ng/mL) as previously described. These differentiated THP-1 cells were stimulated with A ⁇ (1-42) peptides at concentrations ranging from 1 M to 50 M for 5 and 24 hours.
  • THP-1 cells were differentiated using PMA (50 ng/mL) as previously described and stimulated with either LPS (10 ng/mL) or 10 M human A ⁇ (1-42) peptides alone, or in combination with COB-152, COB-187 or 0.1% DMSO solvent for 5 hours. Following incubation, the supernatant was collected and stored at ⁇ 80° C. until assayed for IL-6, TNF- ⁇ , and IL-1 ⁇ protein by ELISA, whereas RNA extracted from the cells was reverse transcribed and subjected to quantitative RT-PCR for quantification of IL-6, TNF- ⁇ , IL-1 ⁇ , IL-1, and IFN- ⁇ mRNA. All experiments were performed at least thrice and in duplicates.
  • RNA extracted from differentiated THP-1 cells treated as previously described was reverse transcribed to cDNA and subjected to quantitative RT-PCR.
  • Relative IL-6, TNF- ⁇ , IL-1 ⁇ , IL-1, and IFN- ⁇ gene expression was determined by normalizing with Hprt1 using the comparative Ct method.
  • cytokine ELISA kits (BD Biosciences, Burlington, N.C.) were used to quantify the levels of secreted IL-6, TNF- ⁇ , and IL-1 protein in the supernatant obtained from differentiated THP-1 cells treated with either LPS (10 ng/mL) or 10 ⁇ M human A ⁇ (1-42) peptides alone, or in combination with COB-152, COB-187 or 0.1% DMSO solvent.
  • the ELISA was performed according to the manufacturer's protocol.
  • the supernatant was diluted with the assay diluent at different ratios as shown in the TABLE 4 below for IL-6, TNF- ⁇ , and IL-1 ⁇ . All samples were tested in duplicates and the results were expressed as Mean ⁇ SD of the cytokine concentration (pg/mL). All results presented were corrected for dilution factor.
  • COB-152 Modulates TLR-4 Signaling by Attenuating IL-6 Production in Murine Macrophages. As shown in FIG. 7 , COB-152 inhibits IL-6 expression in LPS induced RAW macrophages. More specifically, COB-152 dose dependently inhibited IL-6 mRNA production in LPS stimulated murine macrophages. IL-6 expression was measured and normalized to GAPDH/HPRT1 mRNA levels, by quantitative RT-PCR. Data values represent Mean ⁇ SD.
  • a ⁇ Peptides Induce the Production of Inflammatory Cytokines in a Concentration-Dependent Manner.
  • FIGS. 8A-8D there was a concentration-dependent increase in mRNA expression of IL-6, TNF- ⁇ , IL-1 ⁇ , and IL-1 ⁇ in PMA differentiated THP-1 cells stimulated with A ⁇ (1-42) peptides at concentrations ranging from 1 ⁇ M to 50 ⁇ M for 5 and 24 hours. A maximum induction was observed at 25 ⁇ M. Such effect was more pronounced at 5 hours compared to 24 hours. Cytokine expression was measured, and normalized to HPRT1 mRNA levels, by quantitative RT-PCR. Data values represent Mean ⁇ SD.
  • COB-152 and COB-187 Modulate A ⁇ -Induced Inflammatory Cytokine Production in Human Macrophages.
  • FIGS. 9A-9D and 10A-10D there was a dose-dependent decrease in IL-6 and TNF- ⁇ production in PMA differentiated THP-1 human macrophages stimulated with A ⁇ (1-42) peptides (10 ⁇ M) in the presence of COB-152 or COB-187.
  • Secreted IL-6 protein levels ( FIGS. 9B and 9D ) and TNF- ⁇ protein levels ( FIGS. 10B and 10D ) were determined by ELISA, whereas IL-6 mRNA levels ( FIGS. 9A and 9C ) and TNF- ⁇ mRNA levels ( FIGS. 10A and 10C ) were measured and normalized to HPRT1 mRNA levels by quantitative RT-PCR. Data values represent Mean ⁇ SD.
  • COB-152 decreased I1-1 ⁇ protein production in PMA differentiated THP-1 human macrophages stimulated with A ⁇ (1-42) peptides (10 ⁇ M) at a concentration of ⁇ 25 M.
  • COB-187 decreased IL-1 ⁇ protein production in PMA differentiated THP-1 human macrophages stimulated with A ⁇ (1-42) peptides (10 ⁇ M) at a concentration of ⁇ 10 M.
  • Secreted IL-1 ⁇ protein levels FIGS. 11B and 11D
  • IL-1 ⁇ mRNA FIGS. 11A-11C
  • Data values represent Mean ⁇ SD.
  • COB-152 and COB-187 inhibited IL-1 ⁇ and IFN- ⁇ mRNA expression in PMA differentiated THP-1 human macrophages stimulated with A ⁇ (1-42) peptides (10 ⁇ M). More specifically, COB-152 and COB-187 inhibited IL-1 ⁇ and IFN- ⁇ mRNA expression in PMA differentiated THP-1 human macrophages stimulated with A ⁇ (1-42) peptides (10 ⁇ M) in a dose-dependent manner. IL-1 ⁇ and IFN- ⁇ mRNA were measured and normalized to HPRT1 mRNA levels by quantitative RT-PCR. Data values represent Mean ⁇ SD.
  • COB-152 and COB-187 Modulate LPS-Induced Inflammatory Cytokine Production in Human Macrophages.
  • FIGS. 14A-14D and 15A-15D there was a dose-dependent decrease in IL-6 and TNF- ⁇ production in PMA differentiated THP-1 human macrophages stimulated with LPS (10 ng/mL) in the presence of COB-152 or COB-187.
  • Secreted IL-6 protein levels FIGS. 14B and 14D
  • TNF- ⁇ protein levels FIGS. 15B and 15D
  • IL-6 mRNA levels FIGS. 14A and 14C
  • TNF- ⁇ mRNA levels FIGS. 15A and 15C
  • FIG. 16D there was a dose-dependent decrease in IL-1 ⁇ protein production in PMA differentiated THP-1 human macrophages stimulated with LPS (10 ng/mL) in the presence of COB-187.
  • FIG. 16B there was a decrease in IL-1 ⁇ protein production in PMA differentiated THP-1 human macrophages stimulated with LPS (10 ng/mL) in the presence of COB-152 at a concentration of ⁇ 50 M.
  • IL- ⁇ protein levels FIGS. 16B and 16D
  • FIGS. 16A and 16C were measured and normalized to HPRT1 mRNA levels by quantitative RT-PCR. Data values represent Mean ⁇ SD.
  • COB-152 and COB-187 inhibited IL-1 ⁇ mRNA expression in PMA differentiated THP-1 human macrophages stimulated with LPS (10 ng/mL).
  • IL-1 ⁇ mRNA was measured and normalized to HPRT1 mRNA levels by quantitative RT-PCR. Data values represent Mean ⁇ SD.
  • the imidazole and/or thiazole compounds inhibited products of TLR-4 induced signaling.
  • Another known hallmark of GSK-3 inhibition is suppression of immune products (e.g., cytokines) induced by Toll like receptor (TLR) signaling.
  • the I-GSK-3 compounds inhibited products of TLR signaling.
  • the I-GSK-3 compound COB-152 were found to inhibit lipopolysaccharide (i.e., LPS) induction of reactive products (e.g., iNOS) in murine macrophages with an IC 50 of about 160 nM.
  • LPS lipopolysaccharide
  • iNOS reactive products
  • COB-152 inhibited LPS (a known ligand for TLR-4) induction of iNOS transcripts.
  • the IC 50 for COB-152 was determined to be about 160 nM.
  • the ratio of the TC 50 to IC 50 for COB-152 exceeded 100.
  • the samples of FIG. 8 included an untreated sample; LPS—treated with LPS alone; DMSO—treated with LPS and DMSO (carrier control); 0.1 M COB-152—treated with LPS and 0.1 M COB-152; 1 M COB-152—treated with LPS and 1 M COB-152; and 10 M COB-152—treated with LPS and 10 M COB-152.
  • Means of administering active compounds according to embodiments herein include, but are not limited to, oral, sublingual, intravenous, intramuscular, intraperitoneal, percutaneous, intranasal, intrathecal, subcutaneous, or enteral.
  • Local administration to the afflicted site may be accomplished through means known in the art, including, but not limited to, topical application, injection, infusion and implantation of a porous device in which the active compound(s) or compositions described herein are contained.
  • the active compounds described herein will generally be administered as a pharmaceutical composition comprising one or more active compounds described herein in combination with a pharmaceutically acceptable excipient and other formulational aids.
  • compositions may be aqueous solutions, emulsions, creams, ointments, suspensions, gels, liposomal suspensions, and the like.
  • Suitable excipients include water, saline, Ringer's solution, dextrose solution, and solutions of ethanol, glucose, sucrose, dextran, mannose, mannitol, sorbitol, polyethylene glycol (PEG), phosphate, acetate, gelatin, collagen, Carbopol®, vegetable oils, and the like.
  • PEG polyethylene glycol
  • phosphate acetate
  • gelatin collagen
  • Carbopol® vegetable oils
  • One may additionally include suitable preservatives, stabilizers, antioxidants, antimicrobials, and buffering agents, for example, BHA, BHT, citric acid, ascorbic acid, tetracycline, and the like.
  • Cream or ointment bases useful in formulation include lanolin, Silvadene® (Marion), Aquaphor® (Duke Laboratories), and the like.
  • Other devices include indwelling catheters and devices such as the Alzet® minipump.
  • Opthalmic preparations may be formulated using commercially available vehicles such as Sorbi-Care® (Allergan), Neodecdron® (Merck, Sharp & Dohme), Lacrilube®, and the like.
  • active compounds described herein in bulking agents, for example human serum albumin, sucrose, mannitol, and the like.
  • a thorough discussion of pharmaceutically acceptable excipients is available in Remington's Pharmaceutical Sciences I (Mack Pub. Co.), incorporated herein by reference.
  • active compounds and pharmaceutical compositions according to embodiments herein can be administered both orally and parenterally in accordance with conventional procedures for the treatment of autoimmune disease and performance of organ and/or tissue transplantation.
  • the amount of active compound required to treat any particular autoimmune and/or transplant disorder will, of course, vary depending upon the nature and severity of the disorder, the age and condition of the subject, and other factors readily determined by one of ordinary skill in the art.
  • Active compounds are administered in dosage units, preferably divided dosage units, containing the active compound with a suitable physiologically acceptable carrier or excipient, many of which are well known to those in the art and are described above.
  • the dosage units can be in the form of a liquid preparation, e.g., solutions, suspensions, dispersions, or emulsions, or they may be in solid form such as pills, tablets, capsules or the like.
  • Compositions in unit dosage form i.e., pharmaceutical compositions which are available in a pre-measured form suitable for single dose administration without requiring that the individual dosage be measured out by the user, for example, pills, tablets, capsules, or ampoules are particularly preferred methods of administration of the active compounds described herein.
  • compositions in dosage unit form may include an amount of composition which provides from about 0.05 mg to about 60 mg, preferably from about 0.05 mg to about 20 mg, of active compound per day.
  • the active compound according to embodiments herein or a salt thereof is combined, e.g., with solid powdered carriers such as lactose, sucrose, mannitol; starches such as potato starch, corn starch or amylopectin, as well as laminaria powder and citrus pulp powder; cellulose derivatives of gelatin, also lubricants such as magnesium or calcium sterate of polyethylene glycols (carbowaxes) of suitable molecular weights may be added, to form compressed tablets or core tablets for sugar coating.
  • solid powdered carriers such as lactose, sucrose, mannitol
  • starches such as potato starch, corn starch or amylopectin, as well as laminaria powder and citrus pulp powder
  • cellulose derivatives of gelatin also lubricants such as magnesium or calcium sterate of polyethylene
  • the latter are coated, for example, with concentrated sugar solutions which, e.g., can contain gum arabic, talcum and/or titinium dixoide, or they are coated with a lacquer dissolved in easily volatile organic solvents or mixture of organic solvents.
  • Dyestuffs can be added to these coatings, for example, to distinguish between different contents of active substance.
  • Capsules useful herein include, for example, soft gelatin capsules (pearl-shaped closed capsules), geltabs, other capsules which consist, for example, of a mixture of gelatin and glycerin and contain, e.g., mixtures of the active substances or a suitable salt thereof with solid, powdered carriers such as, e.g., lactose, sucrose, sorbital, mannitol; starches such as potato starch corn starch or amylopectin, cellulose derivatives or gelatin, as well as magnesium sterate or steric acid. Suppositories are employed as dosage units for rectal application.
  • gelatin rectal capsules consist of a combination of the active substance or a suitable salt thereof with a neutral fatty base, or also gelatin rectal capsules can be employed which consist of a combination of the active substance or a suitable salt thereof with polyethylene glycols (carbowaxes) of suitable molecular weight.
  • Ampoules for parenteral administration preferably contain an active compound or a water soluble salt thereof and suitable stabilizing agents, and, if necessary, buffer substances in aqueous solution.
  • Anti-oxidizing agents such as sodium bisulfite, sodium sulfite, ascorbic acid or Rongalit (formaldehyde-sodium bisulfite compound), and the like are suitable as stabilizing agents either alone or combined, in total concentrations from about 0.01% to about 0.05% by weight of the composition. Because of its ability to form chelates, ascorbic acid has an additional stabilizing effect; in this function it can also be replaced by other chelate-formers.
  • the best suitability of the active ingredient is attained, e.g., by mixtures in suitable ratio of sodium sulfite, sodium bisulfite and/or ascorbic acid, or by the addition of other buffer substances such as citric acid and/or salts thereof.
  • the ampoules can contain a slight amount of a preservative.
  • the tablets can be sugar coated according to conventional art practices. Colors may be added to the coating.
  • the term “substantially” is utilized herein to represent the inherent degree of uncertainty that may be attributed to any quantitative comparison, value, measurement, or other representation.
  • the term “substantially” is also utilized herein to represent the degree by which a quantitative representation may vary from a stated reference without resulting in a change in the basic function of the subject matter at issue.

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CN106659714A (zh) 2017-05-10
US10392381B2 (en) 2019-08-27
CN106659714B (zh) 2021-06-08
WO2016010609A1 (fr) 2016-01-21
WO2016010611A1 (fr) 2016-01-21
US20200017489A1 (en) 2020-01-16
US20170210737A1 (en) 2017-07-27
US10633377B2 (en) 2020-04-28
US20170196845A1 (en) 2017-07-13
CA2955582C (fr) 2021-03-16
EP3169323A2 (fr) 2017-05-24
JP6648108B2 (ja) 2020-02-14
US10023567B2 (en) 2018-07-17
US20180362521A1 (en) 2018-12-20
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