[go: up one dir, main page]

WO2025147633A2 - Co-agonistes gip/glp-1 et leurs promédicaments associés - Google Patents

Co-agonistes gip/glp-1 et leurs promédicaments associés Download PDF

Info

Publication number
WO2025147633A2
WO2025147633A2 PCT/US2025/010266 US2025010266W WO2025147633A2 WO 2025147633 A2 WO2025147633 A2 WO 2025147633A2 US 2025010266 W US2025010266 W US 2025010266W WO 2025147633 A2 WO2025147633 A2 WO 2025147633A2
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
spacer
dipeptide
peptide
side chain
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/US2025/010266
Other languages
English (en)
Other versions
WO2025147633A3 (fr
Inventor
Richard D. Dimarchi
Fa Zhang
Kishore THALLURI
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Indiana University Research and Technology Corp
Original Assignee
Indiana University Research and Technology Corp
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Indiana University Research and Technology Corp filed Critical Indiana University Research and Technology Corp
Publication of WO2025147633A2 publication Critical patent/WO2025147633A2/fr
Publication of WO2025147633A3 publication Critical patent/WO2025147633A3/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/575—Hormones
    • C07K14/605—Glucagons
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • Pre-proglucagon is a 158 amino acid precursor polypeptide that is processed in different tissues to form a number of different proglucagon-derived peptides, including glucagon, glucagon-like peptide- 1 (GLP-1), glucagon-like peptide-2 (GLP-2) and oxyntomodulin (OXM), that are involved in a wide variety of physiological functions, including glucose homeostasis, insulin secretion, gastric emptying, and intestinal growth, as well as the regulation of food intake.
  • GLP-1 glucagon-like peptide- 1
  • GLP-2 glucagon-like peptide-2
  • OXM oxyntomodulin
  • Glucagon is a 29-amino acid peptide that corresponds to amino acids 33 through 61 of pre-proglucagon, while GLP-1 is produced as a 37-amino acid peptide that corresponds to amino acids 72 through 108 of pre-proglucagon.
  • GLP-1 has different biological activities compared to glucagon. Its actions include stimulation of insulin synthesis and secretion, inhibition of glucagon secretion, and inhibition of food intake. GLP- 1 has been shown to reduce hyperglycemia (elevated glucose levels) in diabetics. Exendin-4, a peptide from lizard venom that shares about 50% amino acid identity with GLP-1, activates the GLP-1 receptor and likewise has been shown to reduce hyperglycemia in diabetics.
  • Glucose-dependent insulinotropic peptide is a 42-amino acid gastrointestinal regulatory peptide that stimulates insulin secretion from pancreatic beta cells in the presence of glucose. It is derived by proteolytic processing from a 133 -amino acid precursor, preproGIP.
  • GIP and GLP-1 are known as incretins, and incretin receptor signaling is known to exert physiologically relevant action critical for glucose homeostasis.
  • GIP and GLP- 1 are secreted from the gut following a meal, and these incretins enhance the physiological response to food including sensation of satiety, insulin secretion, and nutrient disposal.
  • Type 2 diabetes (T2D) patients have impaired incretin responses.
  • Dosing diabetes patients with GLP- 1 analogs has been found to be limited by adverse effects, such as nausea and vomiting, and as a consequence dosing most often cannot reach full efficacy for glycemic control and weight loss.
  • GIP alone has very modest glucose- lowering ability in type 2 diabetic humans.
  • Both native GIP and GLP- 1 are inactivated rapidly by the ubiquitous protease, DPP IV, and therefore, can only be used for short-term metabolic control.
  • Peptides that constitute balanced, full potency agonists at the GLP- 1 and GIP receptors have demonstrated transformative pharmacology in the treatment of metabolic diseases, and most notably reduction in body weight.
  • the most advanced medicine (tirzepatide) is formulated as a subcutaneous injection and administered weekly. This drug requires a scheduled dose titration to minimize adverse gastrointestinal effects, with monthly increments over the course of a five-month period.
  • novel peptides exhibiting agonist activity at both the GLP-1 receptor and the GIP receptor are provided.
  • Peptides having both GIP activity and GLP-1 activity are particularly advantageous for inducing weight loss or preventing weight gain, as well as for treating metabolic syndrome, hyperglycemia, and diabetes.
  • the invention provides methods for inducing weight loss or preventing weight gain, which involve administering to a patient in need thereof an effective amount of a peptide, that exhibits activity at both the GIP receptor and the GLP- 1 receptor.
  • Tirzepatide is a known GIP/GLP- 1 co-agonist peptide that has been approved for medical use in the United States for the treatment of type 2 diabetes and for weight loss. Surprisingly, applicant has discovered that the substitution of the phenylalanine residue at position 6 with an alpha methylated phenylalanine retained activity at the GLP-1 and GPI receptors and had higher potency at those receptors relative to tirzepatide for both the human and mouse GLP-1 and GPI receptors.
  • GIP/GLP- 1 co-agonist peptide comprising the sequence of
  • R20 is COOH or CONH 2 , wherein said P20 spacer comprises the structure: -[COCH 2 (OCH 2 CH 2 )kNH] q -(gamma glutamic acid) p -; wherein k is 2, p is 1 or 2 and q is an integer selected from 1, 2 or 4, optionally wherein k is 2, p is 1 and q is 2.
  • X15 is Glu; Xi6 is Aib; X17 is Thr; X19 is Ala or Gin, and R20 is CONH 2 .
  • X15 is Asp; Xi6 is Lys; X17 is IIe; X19 is Gln, and R20 is CONH 2 .
  • X15 is Glu; Xi6 is Lys; X17 is Thr; X19 is Ala, and R20 is CONH 2 .
  • a prodrug derivative of the GIP/GLP- 1 co- agonist peptide of SEQ ID NO: 1 wherein the peptide is modified by the covalent linkage of one or more dipeptides “A-B’' to an amine of said peptide, wherein A is an amino acid or a hydroxy acid and B is an N-alkylated amino acid linked to said peptide through an amide bond between a carboxyl moiety of B and an amine of the peptide (optionally a primary amine), wherein the side chain of the first amino acid (A) of said dipeptide is acylated with a C16-C20 fatty acid, a C16-C20 phosphonic fatty acid, or a C16-C20 diacid.
  • a prodrug derivative of the GIP/GLP- 1 co- agonist peptide of SEQ ID NO: 1 wherein the peptide is modified by the covalent linkage of two or more dipeptides (A-B) via an amide bond to amino acids located at positions selected from positions 1, 7, 16 and 20, relative to SEQ ID NO: 1.
  • a prodrug derivative of the GIP/GLP-1 co-agonist peptide of SEQ ID NO: 1 wherein the peptide is modified by the covalent linkage of two or more dipeptides (A-B) via an amide bond to amino acids located at positions selected from positions 1 and 7, relative to SEQ ID NO: 1, wherein Xi6 is Aib.
  • the GIP/GLP-1 co-agonist peptide of SEQ ID NO: 1 comprises an isoacyl-Thr at position 7 and dipeptides (A-B) is covalently linked to a primary amine of an amino acid at position 1 and/or position 7 of the peptide of SEQ ID NO: 1, wherein said dipeptide comprise the structure: wherein
  • R1 comprises a side chain of (C1-C4 alkyl )NH 2 , wherein a C16-C30 fatty acid, a C16-C30 phosphonic fatty acid, or a C16-C30 diacid is covalently linked to said side chain, optionally via a P7 spacer;
  • R2 is H, or C1-C4 alkyl
  • R4 and R8 are independently H, D, C1-C4 alkyl, C1-C4 alkenyl, C1-C4 alkenyl,
  • R3 is CD3, C 1 -C 6 alkyl, or R3 and R4 together with the atoms to which they are attached form a pyrrolidine, 3,4-dehydropyrrolidine, a hydroxypyrrolidine, a piperdine or a hydroxypiperdine ring; and
  • R5 is NH 2
  • said P7 spacer is selected from the group consisting of a gamma glutamic acid, a gamma glutamic acid-gamma glutamic acid dipeptide, and a (gamma glutamic acid) z -[COCH 2 (OCH 2 CH 2 )k-NH] q -(gamma glutamic acid) p , wherein z is 0 or 1, k is an integer selected from the range of 2-4 and q and p are independently an integer selected from the range of 0-4, optionally wherein z is 0, k and q are both 2 and p is 1.
  • the prodrug derivative of the GIP/GLP-1 co-agonist peptide of SEQ ID NO: 1 is provided wherein the peptide is modified by the covalent linkage of a dipeptides (A-B) via an amide bond to the N-terminal alpha amine of the amino acid at position 1 and to the primary amine of the isoacyl-Thr at position 7, relative to SEQ ID NO: 1.
  • the dipeptide comprises the structure: wherein
  • R1 comprises a side chain of (C4 alkyl)NH 2 , having a C18-C20 fatty acid, a C18-C20 phosphonic fatty acid, or a Cl 8-C20 diacid covalently linked to said side chain, optionally via a spacer;
  • R2, R4 and R8 are each H;
  • R3 is C 1 -C 6 alkyl
  • R5 is NH 2 , wherein the spacer is -[COCH 2 (OCH 2 CH 2 )k-NH] q -( amma glutamic acid) p , wherein k is 2, q is 1 or 2 and p is 0 or 1.
  • the dipeptide comprises the structure: wherein
  • R1 comprises a side chain of (C4 alkyl)NH 2 , having a C18-C20 fatty acid, a C18-C20 phosphonic fatty acid, or a C18-C20 diacid covalently linked to said side chain, optionally via a spacer;
  • R 2 is H
  • R4 and R 8 are independently D or H;
  • R3 is CD3, or C 1 -C 6 alkyl
  • R5 is NH 2 , wherein the spacer is -[COCH 2 (OCH 2 CH 2 )k-NH] q -( amma glutamic acid) p , wherein k is 2, q is 1 or 2 and p is 0 or 1 , optionally wherein R4 and R 8 are both D and R3 is CD3.
  • a and/or B is an amino acid in the D stereoisomer configuration.
  • A is an amino acid in the D stereoisomer configuration and B is an amino acid in the L stereoisomer configuration.
  • A is an amino acid in the L stereoisomer configuration and B is an amino acid in the D stereoisomer configuration.
  • A is an amino acid in the D stereoisomer configuration and B is an amino acid in the D stereoisomer configuration.
  • A is dLys and B is an N-alkylated amino acid in the L stereoisomer configuration.
  • a prodrug derivative of a GIP/GLP- 1 co-agonist wherein the peptide comprising the sequence of YX2EGTX6TSDYSIX13LDKIAQX20AFVQWLIAGGPSSGAPPPS-R20 (SEQ ID NO: 2) wherein
  • X2 is Aib
  • X6 is alpha methylated Phe
  • X13 is Aib
  • X20 is an amino acid comprising a (C1-C4 alkyl)NH 2 side chain that has been acylated with a C16-C20 acyl group, a C16-C20 phosphonic fatty acid, or a C16-C20 alkyl group, optionally via a first spacer; and
  • R20 is COOH or CONH 2 , wherein a dipeptide is covalently linked via an amide bond to the N-terminal alpha amine of the peptide, wherein the dipeptide comprises the structure: wherein
  • R1 comprises a side chain of (C1-C4 alkyl)NH 2 , wherein a C16-C30 fatty acid, a C16-C30 phosphonic fatty acid, or a C16-C30 diacid is covalently linked to said side chain, optionally via a second spacer;
  • R5 is NH 2 , optionally wherein I) R1 comprises a side chain of (C4 alkyl)NH 2 , having a C18-C20 fatty acid, a C18-C20 phosphonic fatty acid, or a C18-C20 diacid covalently linked to said side chain via a second spacer;
  • R5 is NH 2 , wherein said first and second spacers are independently -[COCH 2 (OCH 2 CH 2 )k-NH] q -(gamma glutamic acid) p , wherein k is 2, q is 1 or 2 and p is 0 or 1 , optionally wherein k is 2 and q is 2 and p is 1 ; or
  • R1 comprises a side chain of (C4 alkyl)NH 2 , having a C18-C20 fatty acid, a C18-C20 phosphonic fatty acid, or a C18-C20 diacid covalently linked to said side chain via a second spacer;
  • R5 is NH 2 , wherein said first and second spacers are independently -
  • X20 is an amino acid comprising a (C1-C4 alkyl)NH 2 side chain that has been acylated with a C16-C20 acyl group, a C16-C20 phosphonic fatty acid, or a C16-C20 alkyl group, optionally via a first spacer; and
  • R1 comprises a side chain of (C1-C4 alkyl)NH 2 , wherein a C16-C30 fatty acid, a C16-C30 phosphonic fatty acid, or a C16-C30 diacid is covalently linked to said side chain, optionally via a second spacer;
  • R2 is H, or C1-C4 alkyl
  • R 8 is H, D, or C1-C4 alkyl
  • R3 is CD3, C 1 -C 6 alkyl, or R3 and R4 together with the atoms to which they are attached form a a pyrrolidine, 3,4-dehydropyrrolidine, a hydroxypyrrolidine, a piperdine or a hydroxypiperdine ring; and
  • R5 is NH 2 , wherein said first and second spacers are independently -[COCH 2 (OCH 2 CH 2 )k-NH] q -(gamma glutamic acid) p , wherein k is 2, q is 1 or 2 and p is 0 or 1 , optionally wherein k is 2 and q is 2 and p is 1 ; optionally wherein
  • R1 comprises a side chain of (C4 alkyl)NH 2 , having a C18-C20 fatty acid, a C18-C20 phosphonic fatty acid, or a C18-C20 diacid covalently linked to said side chain via a second spacer;
  • R2, R4 and R 8 are each H;
  • R3 is C1-C4 alkyl
  • R5 is NH 2 , wherein said first and second spacers are independently -[COCH 2 (OCH 2 CH 2 )k-NH] q -(gamma glutamic acid) p , wherein k is 2, q is 1 or 2 and p is 0 or 1 , optionally wherein k is 2 and q is 2 and p is 1 ; or
  • R1 comprises a side chain of (C4 alkyl)NH 2 , having a C18-C20 fatty acid, a C18-C20 phosphonic fatty acid, or a C18-C20 diacid covalently linked to said side chain via a second spacer;
  • R 2 is H
  • R4 and R 8 are each D
  • R3 is CD3
  • R5 is NH 2 , wherein said first and second spacers are independently -[COCH 2 (OCH 2 CH 2 )k-NH] q -(gamma glutamic acid) p , wherein k is 2, q is 1 or 2 and p is 0 or 1 , optionally wherein k is 2 and q is 2 and p is 1.
  • a prodrug derivative of a GIP/GLP- 1 co-agonist wherein the peptide comprising the sequence of
  • X2 is Aib
  • Xr is alpha methylated Phe
  • X7 is isoacyl-Thr
  • X13 is Aib
  • X20 is an amino acid comprising a (C 1 -C4 alkyl)NH 2 side chain that has been pegylated, optionally via a first spacer, with a straight chain or branched polyethylene glycol chain having a molecular weight ranging from about 20k to about 40k; and
  • R20 is COOH or CONH 2 , wherein a dipeptide is covalently linked via an amide bond to the amine of isoacyl-Thr at position 7 of the peptide, and/or at the N-terminal alpha amine, wherein the dipeptide comprises the structure: wherein
  • R1 comprises a (C1-C4 alkylJNEE side chain that has been pegylated, optionally via a second spacer, with a straight chain or branched polyethylene glycol chain having a molecular weight ranging from about 20k to about 40k;
  • R2 is H, or C1-C4 alkyl
  • R 4 is H, D, C1-C4 alkyl, C1-C4 alkenyl, C1-C4 alkenyl, -(CH 2 ) n CH 2 OH or (C 1 - C 4 alkyl)phenyl, wherein n is an integer selected from 0-2;
  • R 8 is H, D, or C1-C4 alkyl
  • R3 is CD3, C 1 -C 6 alkyl, or R3 and R4 together with the atoms to which they are attached form a a pyrrolidine, 3,4-dehydropyrrolidine, a hydroxypyrrolidine, a piperdine or a hydroxypiperdine ring; and R5 is NH 2 , wherein said first and second spacers are independently -[COCH 2 (OCH 2 CH 2 )k-NH] q -(gamma glutamic acid) p , wherein k is 2, q is 1 or 2 and p is 0 or 1 , optionally wherein k is 2 and q is 2 and p is 1 , optionally wherein
  • R1 comprises a (C1-C4 alkyl)NH 2 side chain that has been pegylated, optionally via a first spacer, with a straight chain or branched polyethylene chain having a combined molecular weight ranging from 20k to 40k;
  • R2, R4 and R 8 are each H;
  • R3 is C1-C4 alkyl
  • R5 is NH 2 , wherein said first and second spacers are independently -[COCH 2 (OCH 2 CH 2 )k-NH] q -(gamma glutamic acid) p , wherein k is 2, q is 1 or 2 and p is 0 or 1 , optionally wherein k is 2 and q is 2 and p is 1 ; or
  • R1 comprises a (C1-C4 alkyl)NH 2 side chain that has been pegylated, optionally via a second spacer, with a straight chain or branched polyethylene chain having a combined molecular weight ranging from 20k to 40k;
  • R 2 is H
  • R4 and R 8 are each D
  • R3 is CD3
  • R5 is NH 2 , wherein said first and second spacers are independently -[COCH 2 (OCH 2 CH 2 )k-NH] q -(alanine-triazole), wherein k is 2, and q is 1 or 2, optionally wherein k is 2, or -[COCH 2 (OCH 2 CH 2 )k-NH] q -(cysteine-S-S), wherein k is 2, and q is 1 or 2, optionally wherein k is 2.
  • said dipeptide is present only at amino acid position 7 of SEQ ID NO: 3; in one embodiment the said dipeptide is located only at the N- terminal alpha amine; and in one embodiment the dipeptide is located at both the N-terminal alpha amine and at amino acid position 7 of SEQ ID NO: 3.
  • the dipeptides of the GIP/GLP-1 co-agonist peptide, and optionally the amino acid at position 20 comprise a branched PEG chain having a molecular weight of 20K or 40K, wherein the branched PEG chain comprises 2, 3, 4 or 5 branches.
  • the dipeptides of the GIP/GLP-1 co-agonist peptide comprise a branched PEG chain, and the amino acid at position 20 comprises a straight chain PEG, a C16-C30 fatty acid, a C16-C30 phosphonic fatty acid, or a C16-C30 diacid.
  • the branched PEG chain construct comprises two branches of 10K each, or two branches of 20K each, optionally linked together via an amino acid extension of lysine residues.
  • the branched polyethylene chain comprises four branches of 5K each, or four branches of 10K each optionally linked together via an amino acid extension of lysine residues.
  • each of the branches of the branched polyethylene chains are covalently linked to the dipeptide(s) of the GIP/GLP-1 co-agonist peptide via a disulfide linkage, wherein the amino acid at position 20 is pegylated via a non-disulfide covalent bond linkage, optionally via a triazole linkage.
  • each of the branches of the branched polyethylene chain are covalently linked to the dipeptide(s), and to the amino acid at position 20, of the GIP/GLP-1 co-agonist peptide via a disulfide linkage. The disulfide linkages enhance metabolism and clearance of the polyethylene glycol.
  • GIP/GLP-1 co-agonist peptide of SEQ ID NO: 3 is provided wherein
  • X20 is an amino acid comprising a (C4 alkyl)NH 2 side chain that has been pegylated via a first spacer, with a straight chain or branched polyethylene glycol chain having a molecular weight ranging from about 20k to about 40k; and
  • R20 is COOH or CONH 2 , wherein a dipeptide is covalently linked via an amide bond to the amine of isoacyl-Thr at position 7 of the peptide, and/or at the N-terminal alpha amine, wherein the dipeptide comprises the structure: wherein
  • R1 comprises a (C4 alkyl)NH 2 side chain that has been pegylated, via a second spacer, with a straight chain or branched polyethylene glycol chain having a molecular weight ranging from about 20k to about 40k;
  • R 2 is H
  • R4 and R 8 are independently D or H;
  • R3 is C1-C4 alkyl or CD3; and R5 is NH 2 , wherein said first and second spacers are independently -[COCH 2 (OCH 2 CH 2 )k-NH] q -(alanine-triazole), wherein k is 2, and q is 1 or 2, optionally wherein k is 2, or -[COCH 2 (OCH 2 CH 2 )k-NH] q -(cysteine-S-S), wherein k is 2, and q is 1 or 2, optionally wherein k is 2.
  • a prodrug derivative of the GIP/GLP-1 co- agonist peptide of SEQ ID NO: 1, SEQ ID NO: 2 or SEQ ID NO: 3 wherein the peptide is modified by the covalent linkage of one or more dipeptides “A-B” and/or sequential dipeptides “A-B-C-D” to an amine of said peptide, wherein A and C are amino acids and B and D are N- alkylated amino acids linked to said peptide through an amide bond between a carboxyl moiety of B (for the dipeptide “A-B”) or D (for the sequential dipeptide “A-B-C-D”) and an amine of the peptide, wherein the side chain of amino acid (A) and (C) is acylated with a C16-C20 fatty acid, a C18-C20 phosphonic fatty acid, or a C16-C20 diacid.
  • one or more amino acids at position 1 are covalently linked via an amide bond to either the dipeptide “A-B” or the sequential dipeptide “A-B-C-D”.
  • R4, R 8 , R24 and R28 are independently H, D, or C1-C4 alkyl
  • a GIP/GLP-1 co-agonist peptide of SEQ ID NO: 3 wherein Xz is Aib;
  • X7 is isoacyl-Thr
  • X13 is Aib
  • X20 is an amino acid comprising a (C4 alkyl)NH 2 side chain that has been pegylated via a first spacer, with a straight chain or branched polyethylene glycol chain having a molecular weight ranging from about 20k to about 40k; and
  • R20 is COOH or CONH 2 , wherein a sequential dipeptide “A-B-C-D” comprising the structure of is covalently linked to the N-terminal alpha amine, wherein
  • R1 comprises a (C4 alkyl)NH 2 side chain that has been pegylated, via a second spacer, with a straight chain or branched polyethylene glycol chain having a molecular weight ranging from about 20k to about 40k;
  • R21 comprises (C4 alkyl)NH 2 or a (C4 alkyl)NH 2 side chain that has been pegylated, via a second spacer, with a straight chain or branched polyethylene glycol chain having a molecular weight ranging from about 20k to about 40k;
  • R2, and R22 are independently H, or C1-C4 alkyl
  • R4, R 8 , R24 and R28 are independently H, D, or C1-C4 alkyl
  • R3 is CD3, C 1 -C 6 alkyl, or R3 and R4 together with the atoms to which they are attached form a substituted or unsubstituted pyrrolidine, hydroxypyridine or piperdine ring;
  • R23 is CD3, C 1 -C 6 alkyl, or R23 and R24 together with the atoms to which they are attached form a substituted or unsubstituted pyrrolidine, hydroxypyridine or piperdine ring, wherein said second and third spacers are independently -[COCH 2 (OCH 2 CH 2 )k-NH]q-(alanine-triazole), wherein k is 2, and q is 1 or 2, optionally wherein k is 2, or -[COCH 2 (OCH 2 CH 2 )k-NH] q -(cysteine-S-S), wherein k is 2, and q is 1 or 2, optionally wherein k is 2.
  • a pharmaceutical composition comprising any of the novel the GIP/GLP-1 co-agonist, or prodrug derivatives thereof, disclosed herein, preferably at a purity level of at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%, and a pharmaceutically acceptable diluent, carrier or excipient.
  • compositions may contain a GIP/GLP-1 co-agonist, or prodrug derivatives thereof, as disclosed herein at a concentration of about lOmg/ml to lOOmg/ml, or about 30mg/ml to about lOOmg/ml or about 50 mg/ml to about lOOmg/ml, or about 40mg/ml, 50mg/ml, 60 mg/ml, 70 mg/ml, 80mg/ml, 90 mg/ml, or 100 mg/ml, or higher.
  • the pharmaceutical compositions comprise aqueous solutions that are sterilized and optionally stored within various package containers.
  • aqueous formulations are prepared in dimethyl sulfoxide (DMSO), including about 30% to 100% DMSO, about 50% to 100%- DMSO, about 70% to 100% DMSO, or about 90% to 100% DMSO, with the remainder water.
  • aqueous formulations are prepared in 100% dimethyl sulfoxide.
  • the pharmaceutical compositions comprise a lyophilized powder.
  • the pharmaceutical compositions can be further packaged as part of a kit that includes a disposable device for administering the composition to a patient. The containers or kits may be labeled for storage at ambient room temperature or at refrigerated temperature.
  • an improved method of treating diabetes in patients in need thereof comprises the steps of administering a GIP/GLP-1 co-agonist, or prodrug derivatives thereof, of the present disclosure in an amount therapeutically effective to lower blood glucose levels.
  • GIP/GLP-1 co- agonist, or prodrug derivatives thereof is acylated with one or more a fatty acid or diacid groups having sufficient size to bind serum albumin with high affinity.
  • an improved method of reducing weight gain or inducing weight loss in patients in need thereof while reducing adverse side effects comprises the steps of administering a GIP/GLP- 1 co-agonist, or prodrug derivatives thereof, of the present disclosure in an amount therapeutically effective reducing weight gain or inducing weight loss in a subject.
  • GIP/GLP-1 co- agonist, or prodrug derivatives thereof is acylated with one or more a fatty acid or diacid groups having sufficient size to bind serum albumin with high affinity.
  • Fig. 1 Provides the structure of a prodrug analog of tirzepatide (TZP): (Tyr-Aib-Glu- Gly-Thr-(Me-Phe)-Thr*-Ser-Asp-Tyr; SEQ ID NO: 5; showing Thr* (aMe-Phe6, Thr7) as a isoacyl-dipeptide-protected prodrug and its conversion to the active parent peptide (SEQ ID NO: 6) by the intramolecular cleavage of the dipeptide through formation of a diketopiperazine the speed of which is controlled by the chemical nature of the dipeptide, and a subsequent comparatively rapid O to N rearrangement generates the amide bond between residues 6 and 7.
  • ZTP tirzepatide
  • Fig. 3 A and 3B demonstrate the activity of prodrug derivatives of the aMe-Phe6 analog of TZP.
  • An in vitro assay was used to detect the agonist activity of aMe-Phe6-TRP, 4062 ( ⁇ ) (SEQ ID NO: 11), aMe-Phe6-TRP with a dipeptide prodrug element linked i) at the Lys side chain at position 16, 4212 ( )SEQ ID NO: 42); ii) at a isoacyl-Thr at position 7, 4210 ( ⁇ ) (SEQ ID NO: SEQ ID Nos: 38 and 39); and iii) at the N-terminal alpha amine, 4083 ( ⁇ ) (SEQ ID NO: 15) for both the GLP-1 receptor (Fig. 3A) and the GIP receptor (Fig. 3B).
  • Figs. 4 A and 4B show the structure of a isoacyl peptide analog of aMe-Phe6-TRP (YXEGT(alpha-Me)FTSDYSIXLDKIAQK((miniPEG)2-yE- COC18H36CO2H)AFVQWLIAGGPSSGAPPPS-NH 2 ; MBX 4062 (Fig.
  • Fig. 8 presents the results from ten days daily dosing in DIO-Rats with prodrug MBX 4071 administered subcutaneously at 10 or 30nmol/kg, respectively to DIO Rats.
  • TZP MBX 4160; SEQ ID NO: 99
  • MBX 4062 the (alpha-Me)-Phe6 TZP analog
  • Observations were made through day 14 with dosing beginning on day 0.
  • the plasma concentration of peptide drug agonists MBX 4060 and MBX 4062 is shown for three representative rats as determined 24 hours following the last administered doses.
  • Figs. 10A-10C provides the PK-results of a single dose, SC-Monkey Study with MBX prodrug co-agonist, MBX 4071 (SEQ ID NOs: 13 and 14) respectively administered at 25, 50 or 75 nmol/kg.
  • the concentration of the prodrug (MBX 4071) and the resultant drug (MBX 4062 (SEQ ID NO: 11)) are shown in Fig. 10A.
  • the structure of MBX 4071 (SEQ ID NOs: 13 and 14) is shown in Fig. 10B and the structure of MBX 4062 (SEQ ID NO: 11) is shown in Fig. 10C.
  • Fig. 12 Compares the in vitro bioactivity of various GIP/GLP-1 co-agonists at the human and mouse GIP and GLP-1 receptors. Results are reported as absolute potency (EC50, pM) at the four receptors. Modifications relative to TZP (MBX 4060; (SEQ ID NO: 99)) are indicated.
  • Fig 17 provides the results of an Inotiv NHP (cynomolgus monkey) PK Analysis Study.
  • the peptides MBX 2101, 4062, and three prodrugs 4269, 4271 and 4272 were subcutaneously injected at 50nmol/kg.
  • the peptide concentration over the course of two weeks was assessed by LCMS, and the resultant drug concentration () for the three prodrugs is reported.
  • Fig 19 provides the results of an Inotiv NHP (cynomolgus monkey) PK Analysis Study.
  • Two prodrugs MBX 4083 and 4269 were subcutaneously injected at 50nmol/kg.
  • the peptide concentration over the course of two weeks was assessed by LCMS, and the resultant respective drug concentration (MBX 4062 and 4268) for the two prodrugs is reported.
  • the administered prodrugs are displayed in closed symbols and the resultant drugs are in open symbols.
  • Fig. 23 provides the speed of conversion in PBS of four prodrugs of MBX 4062 of which two are at the N -terminal amine (MBX 4239 and MBX 4240) and two are at lysine 16 (MBX 4241 and 4242) as a function time, through 21 days of analysis by LCMS.
  • the prodrugs differ by the nature of stereochemistry in the dipeptide and the nature of the second amino acid of the dipeptide.
  • Fig. 24A-24C provides the structure of various GIP/GLP-1 co-agonists.
  • Fig. 24A represents MBX4223 (SEQ ID NO: 49 and 50) having lipids at residues : 7, 16, 20 linked via a cleavable dipeptide (dKSar) at 7, and 16 (wherein the dK is acylated with (miniPEG)2-yE- COC18H36CO2H);
  • dKSar cleavable dipeptide
  • 24B represents MBX4224 (SEQ ID NO: 51 and 52) having lipids at residues: 1, 7, and 20 linked via a cleavable dipeptide (dKSar) at 1 and 7 (wherein the dK is acylated with (miniPEG)2-yE-COC18H36CO2H);
  • Fig. 24C represents MBX4225 (SEQ ID NO: 53) having lipids at residues: 1, 16, and 20 linked via a cleavable dipeptide (dKSar) at 1 and 16 (wherein the dK is acylated with (miniPEG)2-yE-COC18H36CO2H).
  • Figs. 26A & 26B provides an analysis of the conversion of a sequential prodrug TZP analog (MBX4234) to the active drug (MBX4062).
  • Fig. 26A is a table providing the conversion over time in PBS of a single sequential prodrug of MBX 4062 (MBX 4234) where the first DKP formation yields MBX 4083 which is followed by a subsequent DKP formation to form MBX 4062.
  • the analysis was conducted as a function time through 28 days by LCMS.
  • Fig. 26B provides the structure of MBX4234 (SEQ ID NO: 55)).
  • Fig. 28 provides a comparative analysis of the PK results of an Inotiv NHP (cynomolgus monkey) Study.
  • Two prodrugs MBX 4083 (single cleavage) and 4291 (sequential cleavage) were subcutaneously injected at 50nmol/kg.
  • the peptide concentration over the course of three weeks was assessed by LCMS, and the resultant respective drug concentration for the two prodrugs is reported.
  • the administered prodrugs are displayed in closed symbols and the resultant drugs are in open symbols.
  • the compounds tested comprise TZP (MBX 4160; SEQ ID NO: 99) modified to comprise amino acid substitution of alpha-Me-F6, Glul5, Thrl7, Alal9 and a pegylated dipeptide linked to the N-terminal alpha amine of the TZP peptide, wherein the first amino acid of the dipeptide is a pegylated dLys (at position -1, “dK-l’”) and the second amino acid of the dipeptide is an N-methylated glycine (at position 0, “N(Me)G0”).
  • TZP MBX 4160; SEQ ID NO: 99
  • the PEG chains are linked to the dLys at position - 1 via a spacer comprising one of the structures disclosed in embodiment 50, wherein (triazole- PEG 20k) represents a single PEG chain of 20 K linked via a triazole comprising linker, (triazole-PEG 40k) represents a single PEG chain of 40 K linked via a triazole comprising linker, (triazole-PEG 5k)4)), represents a branched PEG chain having four linked branches of 5 K linked to dK- 1 via a triazole comprising linker, and (triazole-PEG 10k)4)), represents a branched PEG chain having four linked branches of 10 K linked to dK-l via a triazole comprising linker.
  • the term “pharmaceutically acceptable carrier” includes any of the standard pharmaceutical carriers, such as a phosphate buffered saline solution, water, emulsions such as an oil/water or water/oil emulsion, and various types of wetting agents.
  • the term also encompasses any of the agents approved by a regulatory agency of the US Federal government or listed in the US Pharmacopeia for use in animals, including humans.
  • Pharmaceutically acceptable base addition salts can be prepared from inorganic and organic bases.
  • Salts derived from inorganic bases include by way of example only, sodium, potassium, lithium, ammonium, calcium and magnesium salts.
  • Salts derived from organic bases include, but are not limited to, salts of primary, secondary and tertiary amines.
  • An alternative desired effect for the glucagon peptides of the present disclosure would include treating hyperglycemia, e.g., as measured by a change in blood glucose level closer to normal, or inducing weight loss/preventing weight gain, e.g., as measured by reduction in body weight, or preventing or reducing an increase in body weight, or normalizing body fat distribution.
  • the amount that is "effective” will vary from subject to subject, depending on the age and general condition of the individual, mode of administration, and the like. Thus, it is not always possible to specify an exact “effective amount.” However, an appropriate "effective" amount in any individual case may be determined by one of ordinary skill in the art using routine experimentation.
  • parenteral means not through the alimentary canal but by some other route such as subcutaneous, intramuscular, intraspinal, or intravenous.
  • purified and like terms relate to the isolation of a molecule or compound in a form that is substantially free of contaminants normally associated with the molecule or compound in a native or natural environment.
  • purified does not require absolute purity; rather, it is intended as a relative definition.
  • purified polypeptide is used herein to describe a polypeptide which has been separated from other compounds including, but not limited to nucleic acid molecules, lipids and carbohydrates.
  • peptide encompasses a sequence of 2 or more amino acids and typically less than 50 amino acids, wherein the amino acids are naturally occurring or non-naturally occurring amino acids.
  • Non-naturally occurring amino acids refer to amino acids that do not naturally occur in vivo but which, nevertheless, can be incorporated into the peptide structures described herein.
  • polypeptide and “protein” are terms that are used interchangeably to refer to a polymer of amino acids, without regard to the length of the polymer. Typically, polypeptides and proteins have a polymer length that is greater than that of "peptides.”
  • substitution refers to the replacement of one amino acid residue by a different amino acid residue.
  • a general reference to a peptide is intended to encompass peptides that have modified amino and carboxy termini.
  • an amino acid chain comprising an amide group in place of the terminal carboxylic acid is intended to be encompassed by an amino acid sequence designating the standard amino acids.
  • a "linker” is a bond, molecule or group of molecules that binds two separate entities to one another. Linkers may provide for optimal spacing of the two entities or may further supply a labile linkage that allows the two entities to be separated from each other. Labile linkages include photocleavable groups, acid-labile moieties, base-labile moieties and enzyme-cleavable groups.
  • a "dimer” is a complex comprising two subunits covalently bound to one another via a linker.
  • dimer when used absent any qualifying language, encompasses both homodimers and heterodimers.
  • a homodimer comprises two identical subunits, whereas a heterodimer comprises two subunits that differ, although the two subunits are substantially similar to one another.
  • charged amino acid refers to an amino acid that comprises a side chain that is negatively charged (i.e., de-protonated) or positively charged (i.e., protonated) in aqueous solution at physiological pH.
  • negatively charged amino acids include aspartic acid, glutamic acid, cysteic acid, homocysteic acid, and homoglutamic acid
  • positively charged amino acids include arginine, lysine and histidine.
  • Charged amino acids include the charged amino acids among the 20 amino acids commonly found in human proteins, as well as atypical or non-naturally occurring amino acids.
  • acidic amino acid refers to an amino acid that comprises a second acidic moiety, including for example, a carboxylic acid or sulfonic acid group.
  • hydroxyproline absent any further elaboration encompasses compounds having the structure: includes the specific compounds 3- hydroxyproline, 4- hydroxyproline and 5- hydroxyproline and all the allo-stereoisomers.
  • beta-Lys is an amino acid having the structure:
  • isoacyl-peptide defines a peptide having an ester linked amino acid.
  • a “isoacyl-Thr” is a threonine residue that is linked to another amino acid via an ester bond, rather than a peptide bond, wherein the ester bond is formed using the side chain hydroxyl group of threonine, serine, hydroxyproline or a hydroxylated amino acid. Accordingly, isoacyl-Thr has the structure: isoacyl-4-hydroxyproline comprises the structure:
  • polyethylene glycol chain refers to mixtures of condensation polymers of ethylene oxide and water, in a branched or straight chain, represented by the general formula H(OCH 2 CH 2 ) n OH, wherein n is and integer ranging from 2-20. Absent any further characterization, the term is intended to include polymers of ethylene glycol with an average total molecular weight selected from the range of 500 to 40,000 Daltons, "polyethylene glycol chain” or “PEG chain” is used in combination with a numeric suffix to indicate the approximate average molecular weight thereof. For example, PEG-5,000 (or PEG 5K) refers to polyethylene glycol chain having a total molecular weight average of about 5,000.
  • pegylated and like terms refers to a compound that has been modified from its native state by linking a polyethylene glycol chain to the compound.
  • a “pegylated glucagon peptide” is a glucagon peptide that has a PEG chain covalently bound to the glucagon peptide.
  • miniPEG or “OEG” defines a functionalized polyethylene compound comprising the structure:
  • heteroalkyl refers to a linear or branched hydrocarbon containing the indicated number of carbon atoms and at least one heteroatom in the backbone of the structure. Suitable heteroatoms for purposes herein include but are not limited to N, S, and O.
  • YX2EGTX6X7SDYSIX13LX15X16X17AX19X20AFVQWLIAGGPSSGAPPPS-R20 (SEQ ID NO: 1), or a peptide that differs from SEQ ID NO: 1 by 1 or 2 amino acid substitutions, optionally wherein the amino acid substitutions are conservative amino acid substitutions wherein
  • X19 is Ala or Gin
  • X20 is an amino acid comprising a (C1-C4 alkyl)NH 2 side chain that has been acylated with a C16-C30 acyl group, a C16-C30 phosphonic fatty acid, or a C16-C30 alkyl group, optionally via a spacer
  • R20 is COOH or CONH 2
  • the spacer is selected from the group consisting of a gamma glutamic acid, a gamma glutamic acid-gamma glutamic acid dipeptide, and a (gamma glutamic acid) z - [COCH 2 (OCH 2 CH 2 )k-NH] q -(gamma glutamic acid) p , wherein z is 0 or 1, k is an integer selected from the range of 2-4 and q and p are independently an integer selected from the range of 0-4, optionally wherein X20 is Lys having a Cl 6 to C20
  • a GIP/GLP-1 receptor co-agonist wherein the peptide comprises the sequence of
  • a prodrug having the general structure of A-B wherein A is an amino acid, or a hydroxy acid and B is an N-alkylated amino acid linked to the GIP/GLP-1 receptor co-agonist through formation of an amide bond between a carboxyl of B (in A-B) and an amine of the GIP/GLP-1 receptor co-agonist.
  • the chemical cleavage half-life of A-B from the GIP/GLP-1 receptor co- agonist is at least about 1 week in PBS under physiological conditions, and in one embodiment the chemical cleavage half-life of A-B from the GIP/GLP-1 receptor co-agonist is at least about 8 days up to 21 days.
  • a and B are selected to inhibit enzymatic cleavage of the A-B dipeptide from the GIP/GLP-1 receptor co-agonist by enzymes found in mammalian serum.
  • a and/or B are selected such that the cleavage of A-B from the GIP/GLP-1 receptor co-agonist in PBS under physiological conditions, is not more than twofold the cleavage half-life of A-B from the GIP/GLP-1 receptor co-agonist in a solution comprising a DPP-IV protease (i.e., cleavage of A-B from the GIP/GLP-1 receptor co-agonist does not occur at a rate more than 2x faster in the presence of DPP-IV protease and physiological conditions relative to identical conditions in the absence of the enzyme).
  • a and/or B is an amino acid in the D stereoisomer configuration.
  • A is an amino acid in the D stereoisomer configuration and B is an amino acid in the L stereoisomer configuration.
  • A is an amino acid in the L stereoisomer configuration and B is an amino acid in the D stereoisomer configuration.
  • A is an amino acid in the D stereoisomer configuration and B is an amino acid in the D stereoisomer configuration.
  • prodrugs of the GIP/GLP-1 receptor co-agonists disclosed herein can be administered as highly effective therapeutics for lowering body weight in obese rodents.
  • These peptides demonstrate a much-sustained duration of pharmacological action that should serve to minimize frequency in human dosing. They also demonstrate a much- reduced peak to trough concentration between injections which supports more precise dosing to achieve maximal efficacy (weight lowering) and minimal toxicity (nausea, flatulence and vomiting).
  • the chemical form of the novel peptides is additionally supportive of non- injectable forms of administration, most notably oral and inhalation.
  • any of the standard routes of administration including intramuscular injection can be used to administer the GIP/GLP-1 receptor co-agonist peptides to a patient.
  • Peptides having both GIP activity and GLP- 1 activity are particularly advantageous for inducing weight loss or preventing weight gain, as well as for treating metabolic syndrome, hyperglycemia, and diabetes.
  • the invention provides methods for inducing weight loss or preventing weight gain, which involve administering to a patient in need thereof an effective amount of a peptide, that exhibits activity at both the GIP receptor and the GLP-1 receptor, optionally in the form of a prodrug.
  • a isoacyl peptide derivative of SEQ ID NO: 1 or SEQ ID NO: 2 wherein an ester bond is formed between the amino acids at position 6 and 7, with the proviso that when an ester bond is formed between the amino acids at position 6 and 7, then the amino acid at position 6 is alpha methylated to stabilize against hydrolytic cleavage of the ester.
  • the amino acid at position 7 is serine or threonine.
  • the amino acid at position 7 is an isoacyl-threonine (SEQ ID NO: 3), wherein the ester bond is formed between the side chain hydroxyl group of threonine and the alpha carboxylic acid group of the amino acid at position 6, and the amino acid at position 6 is an alpha methylated amino acid, optionally wherein the amino acid at position 6 is alpha methyl phenylalanine.
  • a prodrug derivative of any of the GIP/GLP- 1 receptor co-agonist disclosed herein is provided.
  • a GIP/GLP- 1 receptor co-agonist peptides selected from SEQ ID NO: 1, SEQ ID NO: 2 or SEQ ID NO: 3 is provide, wherein said peptide is modified by the covalent linkage of one or more dipeptides (A-B) to an aliphatic primary amine of the peptide, wherein A is an amino acid or a hydroxy acid and B is an N-alkylated amino acid linked to said peptide through an amide bond between a carboxyl moiety of B and an amine of the peptide, wherein the side chain of the first amino acid (A) of said dipeptide is acylated with a C16-C30 fatty acid, a C16-C30 phosphonic fatty acid, or a C16-C30 diacid.
  • a dipeptide prodrug element is covalently linked to an amino acid at position 1, 7 or 16 of SEQ ID NO: 1, SEQ ID NO: 2 or SEQ ID NO: 3. In one embodiment a dipeptide prodrug element is covalently linked to an amino acid at position 1 of SEQ ID NO: 1 or SEQ ID NO: 2. In one embodiment a dipeptide prodrug element is covalently linked to an amino acid at position 1 and 7 of SEQ ID NO: 1 or SEQ ID NO: 3. In one embodiment a dipeptide prodrug element is covalently linked to an amino acid at position 1 and 16 of SEQ ID NO: 1 or SEQ ID NO: 2.
  • a dipeptide prodrug element is covalently linked to an amino acid at position 7 and 16 of SEQ ID NO: 1 or SEQ ID NO: 3. In one embodiment a dipeptide prodrug element is covalently linked to an amino acid at position 1, 7 and 16 of SEQ ID NO: 1 or SEQ ID NO: 3. In one embodiment, the dipeptide linked to the amino acid at position 1 is linked to the N-terminal alpha amine. In one embodiment, the dipeptide linked to the amino acid at position 7 is linked to the alpha amine of a isoacyl-Thr of a isoacyl peptide comprising SEQ ID NO: 1 or SEQ ID NO: 3. In one embodiment, the dipeptide linked to the amino acid at position 16 is linked to the side chain 8-amino group of a lysine residue of SEQ ID NO: 1 or SEQ ID NO: 2.
  • the dipeptide prodrug element comprises the structure: wherein heteroatom selected from the group consisting of N, S and O, or R1 and R2 together with the atoms to which they are attached form a C3-C12 cycloalkyl;
  • R 3 is CD3 or C 1 -Cis alkyl
  • R4 and R 8 are each H or D;
  • R5 is NHRe, or R5 and R2 together with the atoms to which they are attached form a 4, 5 or 6 member heterocyclic ring;
  • Re is H or C1-C4 alkyl
  • R1 is (C1-C4 alkyl)NH 2 , optionally ILys or dLys, acylated with a C16-C20 fatty acid, a C16-C20 phosphonic fatty acid, or a C16-C20 diacid;
  • R5 is NH 2 .
  • R1 comprises a side chain of (C1-C4 alkyl)NH 2 , wherein a C16-C30 fatty acid, a C16-C30 phosphonic fatty acid, or a C16-C30 diacid is covalently linked to said side chain, optionally via a P7 spacer;
  • R 2 , and R 8 are independently H, or C1-C4 alkyl
  • R2, R4 and R 8 are each H;
  • R3 is C 1 -C 6 alkyl
  • R5 is NH 2 , wherein the P7 spacer comprises -[COCH 2 (OCH 2 CH 2 )k-NH] q - (gamma glutamic acid) p , wherein k is 2, q is 1 or 2 and p is 0 or 1.
  • the prodrug derivative of SEQ ID NO: 1 or SEQ ID NO: 3 is provided wherein the P7 spacer is -[COCH 2 (OCH 2 CH 2 )2-NH]-(gamma glutamic acid)-, and the acyl group is a C18-C20 diacid.
  • the P7 dipeptide comprises the structure: wherein
  • R1 comprises a side chain of (C4 alkyl)NH 2 , having a Cl 8-C20 fatty acid, a C18-C20 phosphonic fatty acid, or a C18-C20 diacid covalently linked to said side chain, optionally via said Pl spacer;
  • R 2 is H
  • R4 and R 8 are both D
  • R3 is CD3
  • R5 is NH 2 , wherein said Pl spacer comprises -[COCH 2 (OCH 2 CH 2 )k-NH] q - (gamma glutamic acid) p , wherein k is 2, q is 1 or 2 and p is 0 or 1.
  • the Pl spacer is -[COCH 2 (OCH 2 CH 2 )2-NH]-(gamma glutamic acid)-, and the acyl group is a C18-C20 diacid.
  • a prodrug derivative of SEQ ID NO: 1 or SEQ ID NO: 2 wherein a Pl dipeptide is covalently linked via an amide bond to the N- terminal alpha amine of the peptide, wherein the Pl dipeptide comprises the structure: wherein R1 comprises a side chain of (C1-C4 alkyl)NH 2 , wherein a C16-C30 fatty acid, a C16-C30 phosphonic fatty acid, or a C16-C30 diacid is covalently linked to said side chain, optionally via a Pl spacer;
  • R2, and R 8 are independently H, or C1-C4 alkyl
  • R 4 is H, C1-C4 alkyl, C1-C4 alkenyl, C1-C4 alkenyl, -(CH 2 ) n CH 2 OH or (C1-C4 alkyl)phenyl, wherein n is an integer selected from 0-2;
  • R3 is C 1 -C 6 alkyl, or R3 and R4 together with the atoms to which they are attached form a pyrrolidine, 3,4-dehydropyrrolidine, a hydroxypyrrolidine, a piperdine or a hydroxypiperdine ring; and
  • R5 is NH 2 , wherein said Pl spacer is selected from the group consisting of a gamma glutamic acid, a gamma glutamic acid-gamma glutamic acid dipeptide, and a (gamma glutamic acid)z-[COCH 2 (OCH 2 CH 2 )k-NH] q -(gamma glutamic acid) P , wherein z is 0 or 1, k is an integer selected from the range of 2-4 and q and p are independently an integer selected from the range of 0-4.
  • the Pl dipeptide comprises the structure: wherein
  • R1 comprises a side chain of (C4 alkyl)NH 2 , having a C18-C20 fatty acid, a C18-C20 phosphonic fatty acid, or a C18-C20 diacid covalently linked to said side chain, optionally via said Pl spacer;
  • R2, R4 and R 8 are each H;
  • R3 is C 1 -C 6 alkyl
  • R5 is NH 2 , wherein said Pl spacer comprises -[COCH 2 (OCH 2 CH 2 )k- NH] q -(gamma glutamic acid) p , wherein k is 2, q is 1 or 2 and p is 0 or 1.
  • the Pl spacer is -[COCH 2 (OCH 2 CH 2 )2-NH] -(gamma glutamic acid).
  • the acyl group is a C 18-C20 diacid.
  • the Pl dipeptide comprises the structure: wherein
  • R1 comprises a side chain of (C4 alkyl)NH 2 , having a C18-C20 fatty acid, a C 18-C20 phosphonic fatty acid, or a C 18-C20 diacid covalently linked to said side chain, optionally via said Pl spacer;
  • R2 is H
  • R4 and R 8 are both D
  • R3 is CD3
  • R5 is NH 2 , wherein said Pl spacer comprises -[COCH 2 (OCH 2 CH 2 )k-NH] q - (gamma glutamic acid) p , wherein k is 2, q is 1 or 2 and p is 0 or 1.
  • the Pl spacer is -[COCH 2 (OCH 2 CH 2 )2-NH]-(gamma glutamic acid)-, and the acyl group is a C18-C20 diacid.
  • a prodrug derivative of SEQ ID NO: 2 wherein said peptide comprising the sequence of
  • R20 is COOH or CONH 2 ;
  • X2 is Aib
  • Xe is alpha methylated Phe
  • X13 is Aib
  • X20 is Lys having a C16 to C18 fatty acid, a C16-C18 phosphonic fatty acid, or a Cl 6 to C20 diacid linked to the lysine side chain via a P20 spacer comprising the structure: -[COCH 2 (OCH 2 CH 2 )kNH] q -(gamma glutamic acid) p - wherein k is 2, and p and q are independently an integer selected from 1 or 2, further wherein a Pl dipeptide is covalently linked via an amide bond to the N-terminal alpha amine of said peptide, wherein the Pl dipeptide comprising the structure: wherein
  • R1 comprises a side chain of (C4 alkyl)NH 2 , having a C18-C20 fatty acid, a C18-C20 phosphonic fatty acid, or a C18-C20 diacid covalently linked to said side chain via a P 1 spacer;
  • R 2 is H;
  • R4 and R 8 are independently H, D, C1-C4 alkyl, C1-C4 alkenyl, C1-C4 alkenyl, - (CH 2 ) CH 2 OH or (C1-C4 alkyl)phenyl, wherein n is an integer selected from 0-2;
  • R3 is CD3, C 1 -C 6 alkyl, or R3 and R4 together with the atoms to which they are attached form a a pyrrolidine, 3,4-dehydropyrrolidine, a hydroxypyrrolidine, a piperdine or a hydroxypiperdine ring; and
  • the first amino acid of the dipeptide prodrug element is an amino acid in the D- configuration, optionally wherein the amino acid is dLys.
  • the prodrug A-B is provided wherein R3 and R4 together with the atoms to which they are attached form a piperdine ring.
  • a prodrug derivative wherein a sequential dipeptide structure of is covalently linked via an amide bond to said peptide of SEQ ID NO: 1, SEQ ID NO: 2 or SEQ ID NO: 3 at one or more of amino acid positions 1, 7, or 16, wherein
  • R1 is selected from an acylated amino acid having a side chain comprising (C1-C4 alkyl)NH 2 covalently linked to a C16-C30 fatty acid, a C16-C30 phosphonic fatty acid, or a C16-C30 diacid, optionally via a DD1 spacer
  • R 21 is selected from an acylated amino acid having a side chain comprising (C1-C4 alkyl)NH 2 covalently linked to a C16-C30 fatty acid, a C16-C30 phosphonic fatty acid, or a C16-C30 diacid, optionally via a DD2 spacer;
  • R2, and R22 are independently H, or C1-C4 alkyl
  • R3 and R23 are independently CD3, C 1 -C 6 alkyl, or R3 and R4 together with the atoms to which they are attached form a substituted or unsubstituted pyrrolidine, hydroxypyridine or piperdine ring, wherein said DD1 and DD2 spacers are independently selected from the group consisting of a gamma glutamic acid, a gamma glutamic acid-gamma glutamic acid dipeptide, and a (gamma glutamic acid) z -[COCH 2 (OCH 2 CH 2 )k-NH] q -(gamma glutamic acid) p , wherein z is 0 or 1 , k is an integer selected from the range of 2-4 and q and p are independently an integer selected from the range of 0-4.
  • R1 comprises a side chain of (C1-C4 alkyl)NH 2 , wherein a C16-C30 fatty acid, a C16-C30 phosphonic fatty acid, or a C16-C30 diacid is covalently linked to said side chain, optionally via a Pl spacer;
  • R 4 is H, D, C1-C4 alkyl, C1-C4 alkenyl, C1-C4 alkenyl, -(CH 2 ) n CH 2 OH or (C 1 - C4 alkyl)phenyl, wherein n is an integer selected from 0-2;
  • the spacer is any moiety with suitable reactive groups for attaching acyl or alkyl groups.
  • the spacer comprises an amino acid, a dipeptide, a tripeptide, a hydrophilic bifunctional, or a hydrophobic bifunctional spacer.
  • the spacer is selected from the group consisting of: Trp, Glu, Asp, Cys and a spacer comprising NH 2 (CH 2 CH 2 O)n(CH 2 )mCOOH, wherein m is any integer from 1 to 6 and n is any integer from 2 to 12.
  • Such acylated or alkylated glucagon peptides may also further comprise a hydrophilic moiety, optionally a polyethylene glycol.
  • Any of the foregoing GIP/GLP-1 co-agonists peptides may comprise two acyl groups or two alkyl groups, or a combination thereof.
  • the acyl group of the acylated GIP/GLP-1 co-agonist peptide can be of any size, e.g., any length carbon chain, and can be linear or branched.
  • the acyl group is a C8 to C30 fatty acid, a C8-C30 phosphonic fatty acid, or a C8 to C30 diacid.
  • the acyl group can be any of a C8 fatty acid, CIO fatty acid/diacid, C12 fatty acid/diacid, C14 fatty acid/diacid, C16 fatty acid/diacid, C18 fatty acid/diacid, C20 fatty acid/diacid, C22 fatty acid/diacid, C24 fatty acid/diacid, C26 fatty acid/diacid, C28 fatty acid/diacid, or a C30 fatty acid/diacid.
  • the acyl group is a C8 to C20 fatty acid/diacid, e.g., a C18 fatty acid/diacid or a C20 fatty acid/diacid. In some embodiments, the acyl group is a C8 to C20 phosphonic fatty acid, e.g., a Cl 8 phosphonic fatty acid or a C20 phosphonic fatty acid.
  • compositions comprising the GIP/GLP-1 co-agonist peptides, or prodrug derivatives thereof, as disclosed herein can be formulated and administered to patients to using standard pharmaceutically acceptable carriers and routes of administration known to those skilled in the art. Accordingly, the present disclosure also encompasses pharmaceutical compositions comprising one or more of the GIP/GLP-1 co-agonist peptides, or prodrug derivatives thereof, as disclosed herein, in combination with a pharmaceutically acceptable carrier.
  • a pharmaceutical composition comprising any of the novel GIP/GLP-1 co-agonist peptides, or prodrug derivatives thereof, as disclosed herein, preferably sterile and preferably at a purity level of at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%, and a pharmaceutically acceptable diluent, carrier or excipient.
  • compositions may contain a bioactive peptide prodrug derivative as disclosed herein, wherein the resulting active peptide is present at a concentration of at least 0.5 mg/ml, 1 mg/ml, 2 mg/ml, 3 mg/ml, 4 mg/ml, 5 mg/ml, 6 mg/ml, 7 mg/ml, 8 mg/ml, 9 mg/ml, 10 mg/ml, 11 mg/ml, 12 mg/ml, 13 mg/ml, 14 mg/ml, 15 mg/ml, 16 mg/ml, 17 mg/ml, 18 mg/ml, 19 mg/ml, 20 mg/ml, 21 mg/ml, 22 mg/ml, 23 mg/ml, 24 mg/ml, 25 mg/ml or higher.
  • the pharmaceutical composition can comprise any pharmaceutically acceptable ingredient, including, for example, acidifying agents, additives, adsorbents, aerosol propellants, air displacement agents, alkalizing agents, anticaking agents, anticoagulants, antimicrobial preservatives, antioxidants, antiseptics, bases, binders, buffering agents, chelating agents, coating agents, coloring agents, desiccants, detergents, diluents, disinfectants, disintegrants, dispersing agents, dissolution enhancing agents, dyes, emollients, emulsifying agents, emulsion stabilizers, fillers, film forming agents, flavor enhancers, flavoring agents, flow enhancers, gelling agents, granulating agents, humectants, lubricants, mucoadhesives, ointment bases, ointments, oleaginous vehicles, organic bases, pastille bases, pigments, plasticizers, polishing agents, preservatives, sequestering agents, skin penet
  • the pharmaceutical composition comprises any one or a combination of the following components: acacia, acesulfame potassium, acetyltributyl citrate, acetyltriethyl citrate, agar, albumin, alcohol, dehydrated alcohol, denatured alcohol, dilute alcohol, aleuritic acid, alginic acid, aliphatic polyesters, alumina, aluminum hydroxide, aluminum stearate, amylopectin, a-amylose, ascorbic acid, ascorbyl palmitate, aspartame, bacteriostatic water for injection, bentonite, bentonite magma, benzalkonium chloride, benzethonium chloride, benzoic acid, benzyl alcohol, benzyl benzoate, bronopol, butylated hydroxyanisole, butylated hydroxytoluene, butylparaben, butylparaben sodium, calcium alginate, calcium ascorbate, calcium
  • the pharmaceutical formulations disclosed herein may be designed to be short-acting, fast-releasing, long-acting, or sustained-releasing as described below.
  • the pharmaceutical formulations may also be formulated for immediate release, controlled release or for slow release.
  • the instant compositions may further comprise, for example, micelles or liposomes, or some other encapsulated form, or may be administered in an extended-release form to provide a prolonged storage and/or delivery effect.
  • the disclosed pharmaceutical formulations may be administered according to any regime including, for example, daily (1 time per day, 2 times per day, 3 times per day, 4 times per day, 5 times per day, 6 times per day), every two days, every three days, every four days, every five days, every six days, weekly, bi-weekly, every three weeks, monthly, or bi-monthly.
  • the foregoing component(s) may be present in the pharmaceutical composition at any concentration, such as, for example, at most B, wherein B is 90% w/v, 80% w/v, 70% w/v, 60% w/v, 50% w/v, 40% w/v, 30% w/v, 20% w/v, 10% w/v, 5% w/v, 2% w/v, 1% w/v, 0.1% w/v, 0.001% w/v, or 0.0001%.
  • the foregoing component(s) may be present in the pharmaceutical composition at any concentration range, such as, for example from about A to about B. In some embodiments, A is 0.0001% and B is 90%.
  • the pharmaceutical compositions may be formulated to achieve a physiologically compatible pH.
  • the pH of the pharmaceutical composition may be at least 5, at least 5.5, at least 6.5, at least 7, at least 7.5, at least 8, at least 8.5, at least 9, at least 9.5, at least 10, or at least 10.5 up to and including pH 11, depending on the formulation and route of administration.
  • the pharmaceutical compositions may comprise buffering agents to achieve a physiological compatible pH.
  • the buffering agents may include any compounds capable of buffering at the desired pH such as, for example, phosphate buffers (e.g. PBS), triethanolamine, Tris, bicine, TAPS, tricine, HEPES, TES, MOPS, PIPES, cacodylate, MES, and others.
  • the strength of the buffer is at least 0.5 mM, at least 1 mM, at least 5 mM, at least 10 mM, at least 20 mM, at least 30 mM, at least 40 mM, at least 50 mM, at least 60 mM, at least 70 mM, at least 80 mM, at least 90 mM, at least 100 mM, at least 120 mM, at least 150 mM, or at least 200 mM. In some embodiments, the strength of the buffer is no more than 300 mM (e.g.
  • At most 200 mM at most 100 mM, at most 90 mM, at most 80 mM, at most 70 mM, at most 60 mM, at most 50 mM, at most 40 mM, at most 30 mM, at most 20 mM, at most 10 mM, at most 5 mM, at most 1 mM).
  • the pharmaceutical compositions comprise aqueous solutions that are sterilized and optionally stored within various containers.
  • aqueous formulations of the GIP/GLP-1 co-agonist, or prodrug derivatives thereof are prepared at concentrations of about 30mg/ml to about lOOmg/ml in dimethyl sulfoxide (DMSO), including about 30% to 100% DMSO, about 50% to 100% DMSO, about 70% to 100% DMSO, or about 90% to 100% DMSO, with the remainder water.
  • aqueous formulations are prepared in 100% dimethyl sulfoxide.
  • the compounds of the present invention can be used in accordance with some embodiments to prepare pre- formulated solutions ready for injection.
  • prodrug compounds include all pharmaceutically acceptable salts thereof.
  • the kit is provided with a device for administering the prodrug composition to a patient.
  • the kit may further include a variety of containers, e.g., vials, tubes, bottles, and the like.
  • the kits will also include instructions for use.
  • the administrating element of the kit is an aerosol dispensing device, wherein the composition is prepackaged within the aerosol device.
  • the kit comprises a syringe and a needle, and in some embodiments the prodrug composition is prepackaged within the syringe.
  • the present GIP/GLP-1 co-agonists, and the prodrug derivatives thereof have use in the treatment of diabetes, metabolic syndrome and for reducing weight gain or inducing weight loss.
  • Pharmaceutical compositions comprising the GIP/GLP-1 co-agonists, and the prodrug derivatives thereof, and salts thereof, can be administered by any standard route including by oral or inhalation administration.
  • the present disclosure also encompasses multimers of the GIP/GLP-1 co-agonist peptides disclosed herein.
  • Two or more of the GIP/GLP-1 co-agonist peptides can be linked together using standard linking agents and procedures known to those skilled in the art.
  • dimers can be formed between two GIP/GLP-1 co-agonist peptides through the use of bifunctional thiol crosslinkers and bi-functional amine crosslinkers, particularly for the GIP/GLP-1 co-agonist peptides comprising cysteine, lysine ornithine, homocysteine or acetyl phenylalanine residues.
  • the dose of the composition of the present disclosures should be sufficient to stimulate cAMP secretion from cells as described herein or sufficient to decrease blood glucose levels, fat levels, food intake levels, or body weight of a mammal, in a period of from about 1 to 4 minutes, 1 to 4 hours or 1 to 4 weeks or longer, e.g., 5 to 20 or more weeks, from the time of administration. In certain embodiments, the time period could be even longer.
  • the dose will be determined by the efficacy of the particular composition of the present disclosure and the condition of the animal (e.g., human), as well as the body weight of the animal (e.g., human) to be treated.
  • GLP- 1 and exendin-4 have been shown to have some neuroprotective effect.
  • the present disclosures also provides uses of the compositions described herein in treating neurodegenerative diseases, including but not limited to Alzheimer’s disease, Parkinson's disease, Multiple Sclerosis, Amylotrophic Lateral Sclerosis, other demyelination related disorders, senile dementia, subcortical dementia, arteriosclerotic dementia, AIDS-associated dementia, or other dementias, a central nervous system cancer, traumatic brain injury, spinal cord injury, stroke or cerebral ischemia, cerebral vasculitis, epilepsy, Huntington's disease, Tourette's syndrome, Guillain Barre syndrome, Wilson disease, Pick's disease, neuroinflammatory disorders, encephalitis, encephalomyelitis or meningitis of viral, fungal or bacterial origin, or other central nervous system infections, prion diseases, cerebellar ataxias, cerebellar degeneration, spinocerebellar degeneration syndromes, Friedreichs ataxia, ataxia tel
  • compositions are used in conjunction with parenteral administration of nutrients to non-diabetic patients in a hospital setting, e.g., to patients receiving parenteral nutrition or total parenteral nutrition.
  • parenteral administration of nutrients to non-diabetic patients in a hospital setting, e.g., to patients receiving parenteral nutrition or total parenteral nutrition.
  • Nonlimiting examples include surgery patients, patients in comas, patients with digestive tract illness, or a nonfunctional gastrointestinal tract (e.g.
  • compositions comprising the GIP/GLP-1 co-agonist and as disclosed herein, and the parenteral nutrition composition can be administered at the same time, at different times, before, or after each other, provided that the composition is exerting the desired biological effect at the time that the parenteral nutrition composition is being digested.
  • the parenteral nutrition may be administered, 1 , 2 or 3 times per day, while the composition is administered once every other day, three times a week, two times a week, once a week, once every 2 weeks, once every 3 weeks, or once a month.
  • kits comprising a GIP/GLP- 1 co-agonist peptide.
  • the kit comprises a GIP/GLP-1 co-agonist which exhibits at least 0.1% activity of native GIP at the GIP receptor and at least 0.1% activity of native GLP-1 at the GLP-1 receptor.
  • the GIP/GLP-1 co-agonist is packaged in containers, e.g., vials, tubes, bottles, single or multi-chambered pre-filled syringes, cartridges, infusion pumps (external or implantable), jet injectors, pre-filled pen devices and the like.
  • the GIP/GLP-1 co-agonist is provided in the kit as a lyophilized form or in an aqueous solution.
  • the kits in some embodiments comprise instructions for use.
  • the kit is provided with a device for administering the composition to a patient, e.g., syringe needle, pen device, jet injector or another needle-free injector.
  • the administrating element of the kit is an aerosol dispensing device, wherein the composition is prepackaged within the aerosol device.
  • the kit comprises a syringe and a needle, and in one embodiment the sterile composition is prepackaged within the syringe.
  • the kit comprises a pharmaceutically acceptable carrier, such as any of those described herein.
  • a peptide having GIP/GLP-1 co- agonist activity comprising the sequence of
  • X7 is Thr or isoacyl-Thr
  • a prodrug derivative of the peptide of any one of embodiments 1-15 wherein said peptide is modified by the covalent linkage of one or more dipeptides (A-B) to an amine of said peptide, wherein A is an amino acid or a hydroxy acid and B is an N-alkylated amino acid linked to said peptide through an amide bond between a carboxyl moiety of B and an amine of the peptide, wherein the side chain of the first amino acid (A) of said dipeptide is acylated with a C16-C30 fatty acid, C16-C30 phosphonic fatty acid, or a C16-C30 diacid.
  • A is an amino acid or a hydroxy acid
  • B is an N-alkylated amino acid linked to said peptide through an amide bond between a carboxyl moiety of B and an amine of the peptide
  • the side chain of the first amino acid (A) of said dipeptide is acylated with a C
  • R3 is CD3, C1-C6 alkyl, or R3 and R4 together with the atoms to which they are attached form a pyrrolidine, 3,4-dehydropyrrolidine, a hydroxypyrrolidine, a piperdine or a hydroxypiperdine ring; and
  • a prodrug derivative of any one of embodiments 16-18 wherein the GIP/GLP-1 co-agonist peptide comprises the covalent linkage of a dipeptides (A-B) via an amide bond to the N-terminal alpha amine of the amino acid at position 1 and to the primary amine of the isoacyl-Thr at position 7, relative to SEQ ID NO: 1.
  • X7 is isoacyl-Thr; and a dipeptide (A-B) is covalently linked to a primary amine of the isoacyl-Thr at position 7 (a “P7 dipeptide”) and optionally to N-terminal alpha amine at position 1 (a “Pl dipeptide”), wherein said dipeptide comprises the structure: wherein R1 comprises a side chain of (C1-C4 alkyl)NH 2 , wherein a C16-C30 fatty acid, a C16-C30 phosphonic fatty acid, or a C16-C30 diacid is covalently linked to said side chain, optionally via a P7 spacer;
  • R2 is H, or C1-C4 alkyl
  • R4 and R 8 are independently H, D, C1-C4 alkyl, C1-C4 alkenyl, C1-C4 alkenyl, C1-C4 alkenyl, -(CH 2 ) n CH 2 OH or (C1-C4 alkyl)phenyl, wherein n is an integer selected from 0-2;
  • R5 is NH 2
  • said P7 spacer is selected from the group consisting of a gamma glutamic acid, a gamma glutamic acid-gamma glutamic acid dipeptide, and a (gamma glutamic acid) z -[COCH 2 (OCH 2 CH 2 )k-NH] q -(gamma glutamic acid) p , wherein z is 0 or 1 , k is an integer selected from the range of 2-4 and q and p are independently an integer selected from the range of 0-4.
  • a prodrug derivative of embodiments 20 wherein the peptide is modified by the covalent linkage of a dipeptides (A-B) via an amide bond to the N-terminal alpha amine of the amino acid at position 1 and to the primary amine of the isoacyl-Thr at position 7, relative to SEQ ID NO: 1.
  • a prodrug derivative of any one of embodiments 16-18 wherein said dipeptides (A-B) are covalently linked to said peptide at two or more amino acids located at positions independently selected from positions 1, 7, and 16, relative to SEQ ID NO: 1.
  • the prodrug derivative of embodiment 16 or 17 wherein said dipeptide (A-B) is covalently linked to one or more amino acids located at positions 1, 7 and/or 16 of said peptide, wherein said dipeptide (A-B) comprises the structure: wherein
  • R1 comprises a side chain of (C4 alkyl)NH 2 , having a C18-C20 fatty acid, a C18-C20 phosphonic fatty acid, or a C18-C20 diacid covalently linked to said side chain, optionally via said Pl spacer;
  • R5 is NH 2
  • said Pl spacer comprises -[COCH 2 (OCH 2 CH 2 )k-NH] q - (gamma glutamic acid) p , wherein k is 2, q is 1 or 2 and p is 0 or 1, optionally wherein R 3 is CH 3 .
  • R1 comprises a side chain of (C4 alkyl)NH 2 , having a C18-C20 fatty acid, a C18-C20 phosphonic fatty acid, or a C18-C20 diacid covalently linked to said side chain, optionally via said Pl spacer;
  • R3 is CD 3 ;
  • R5 is NH 2 , wherein said P7 spacer comprises -[COCH 2 (OCH 2 CH 2 )k-NH] q - (gamma glutamic acid) p , wherein k is 2, q is 1 or 2 and p is 0 or 1.
  • acyl group is a C18-C20 diacid.
  • the prodrug derivative of any one of embodiments 16-29 wherein a Pl 6 dipeptide is covalently linked via an amide bond to side chain amine of an amino acid located at position 16 relative to SEQ ID NO: 1, wherein said Pl 6 dipeptide comprising the structure: wherein R1 comprises a side chain of (C1-C4 alkyl)NH 2 , wherein a C16-C30 fatty acid, a C16-C30 phosphonic fatty acid, or a C16-C30 diacid is covalently linked to said side chain, optionally via a Pl 6 spacer;
  • X20 is an amino acid comprising a (C1-C4 alkyl)NH 2 side chain that has been pegylated, optionally via a first spacer, with a straight chain or branched polyethylene glycol chain having a molecular weight ranging from about 20k to about 40k; and
  • R20 is CONH 2 , wherein a dipeptide is covalently linked via an amide bond to i) the amine of isoacyl-Thr at position 7 of the peptide; ii) the N-terminal alpha amine; iii) the side chain of the amino acid at position 16; iv) i) and ii); v) i) and iii) vi) i), ii) and iii), wherein the dipeptide comprises the structure: wherein
  • R 4 is H, D, C1-C4 alkyl, C1-C4 alkenyl, C1-C4 alkenyl, -(CH 2 ) n CH 2 OH or (C 1 - C4 alkyl)phenyl, wherein n is an integer selected from 0-2;
  • R 8 is H, D, or C1-C4 alkyl
  • R3 is CD3, C 1 -C 6 alkyl, or R3 and R4 together with the atoms to which they are attached form a a pyrrolidine, 3,4-dehydropyrrolidine, a hydroxypyrrolidine, a piperdine or a hydroxypiperdine ring; and
  • R2, R 4 and R 8 are each H;
  • a prodrug derivative of a peptide having GIP/GLP-1 co-agonist activity is provided, wherein said peptide comprises the sequence of
  • R1 comprises a side chain of (C4 alkyl)NH 2 , having a C18-C20 fatty acid, a C18-C20 phosphonic fatty acid, or a C18-C20 diacid covalently linked to said side chain via a Pl spacer;
  • R 2 is H
  • R4 and R 8 are independently H, D, C1-C4 alkyl, C1-C4 alkenyl, C1-C4 alkenyl, - (CH 2 )nCH 2 OH or (C1-C4 alkyl)phenyl, wherein n is an integer selected from 0-2;
  • R3 is CD3, C 1 -C 6 alkyl, or R3 and R4 together with the atoms to which they are attached form a pyrrolidine, 3,4-dehydropyrrolidine, a hydroxypyrrolidine, a piperdine or a hydroxypiperdine ring; and
  • R5 is NH 2 , wherein said Pl spacer and P20 spacer are independently [COCH 2 (OCH 2 CH 2 )k-NH] q -(gamma glutamic acid) p , wherein k is 2, q is 1 or 2 and p is 0 or 1 , optionally wherein R4 and R 8 are each H, and R3 is CH3 or CH 2 CH3, or R4 and R 8 are each D and R3 is CD3.
  • the prodrug derivative of any one of embodiments 16-34 is provided wherein Xi6 is Lys, modified by the covalent linkage of a P16 dipeptide (A-B) to the side chain amine via an amide bond, wherein said P16 dipeptide comprises the structure: wherein
  • R1 comprises a side chain of (C1-C4 alkyl)NH 2 , wherein a C16-C30 fatty acid, a C18-C20 phosphonic fatty acid, or a C16-C30 diacid is covalently linked to said side chain, optionally via a Pl 6 spacer;
  • R2 is H, or C1-C4 alkyl
  • R4 and R 8 are independently H, D, C1-C4 alkyl, C1-C4 alkenyl, C1-C4 alkenyl, - (CH 2 ) n CH 2 OH or (C1-C4 alkyl)phenyl, wherein n is an integer selected from 0-2;
  • R3 is CD3, C 1 -C 6 alkyl, or R3 and R4 together with the atoms to which they are attached form a pyrrolidine, 3,4-dehydropyrrolidine, a hydroxypyrrolidine, a piperdine or a hydroxypiperdine ring; and
  • R5 is NH 2 , wherein said P16 spacer is selected from the group consisting of a gamma glutamic acid, a gamma glutamic acid-gamma glutamic acid dipeptide, and a (gamma glutamic acid) z -[COCH 2 (OCH 2 CH 2 )k-NH] q -(gamma glutamic acid) p , wherein z is 0 or 1, k is an integer selected from the range of 2-4 and q and p are independently an integer selected from the range of 0-4.
  • R1 comprises a side chain of (C4 alkyl)NH 2 , having a C18-C20 fatty acid, a C18-C20 phosphonic fatty acid, or a C18-C20 diacid covalently linked to said side chain, optionally via said Pl 6 spacer;
  • R2, R4 and R 8 are each H;
  • R1 comprises a side chain of (C4 alkyl)NH 2 , having a C18-C20 fatty acid, a C 18-C20 phosphonic fatty acid, or a C 18-C20 diacid covalently linked to said side chain, optionally via said Pl 6 spacer;
  • R2 is H
  • R3 is CD3
  • R3 and R4 together with the atoms to which they are attached form a piperdine ring.
  • X 2 is Aib
  • Xe is alpha methylated Phe
  • X7 is Thr or isoacyl-Thr
  • X13 is Aib
  • X 2 o is an amino acid comprising a (Cl -C8 alkyl)NH 2 side chain that has been acylated with a C16-C30 acyl group, a C16-C30 phosphonic fatty acid, or a C16-C30 alkyl group, optionally via a P20 spacer;
  • R20 is COOH or CONH 2 , wherein a Pl dipeptide is covalently linked via an amide bond to the N-terminal alpha amine of said peptide, said Pl dipeptide comprising the structure: wherein
  • R1 comprises a side chain of (C4 alkyl)NH 2 , having a C18-C20 fatty acid, a C18-C20 phosphonic fatty acid, or a C18-C20 diacid covalently linked to said side chain via a P 1 spacer;
  • R 2 is H
  • R4 and R 8 are each D
  • R3 is CD3
  • R1 comprises a side chain of (C4 alkyl)NH 2 , having a C18-C20 fatty acid, a C18-C20 phosphonic fatty acid, or a C18-C20 diacid covalently linked to said side chain via a P 1 spacer;
  • R 2 R4 and R 8 are each H;
  • R3 is CH3
  • R5 is NH 2 , wherein said Pl spacer and P20 spacer are independently -[COCH 2 (OCH 2 CH 2 )k-NH] q -(gamma glutamic acid) p , wherein k is 2, q is 1 or 2 and p is 0 or 1 , optionally wherein k is 2 and q is 2 and p is 1.
  • any one or more of the Pl, P7 or Pl 6 dimers comprises a sequential dipeptide structure of covalently linked via an amide bond to said peptide, wherein
  • R1 is comprises (C1-C4 alkyl)NH 2 covalently linked to a C16-C30 fatty acid, a C16-C30 phosphonic fatty acid, or a C16-C30 diacid, optionally via a DD1 spacer;
  • R21 is (C1-C4 alkyl)NH 2 or comprises (C1-C4 alkyl)NH 2 covalently linked to a C16-C30 fatty acid, C16-C30 phosphonic fatty acid, or a C16-C30 diacid, optionally via a DD2 spacer;
  • R1 comprises (C1-C4 alkyl)NH 2 covalently linked to a C16-C30 fatty acid, a
  • R21 comprises (C1-C4 alkyl)NH 2 covalently linked to a C16-C30 fatty acid, C16-C30 phosphonic fatty acid, or a C16-C30 diacid, optionally via a DD2 spacer;
  • R2, R4, R 8 R22, R24 and R2 are each H;
  • R1 comprises (C1-C4 alkyl)NH 2 covalently linked to a C16-C20 fatty acid, a C18-C20 phosphonic fatty acid, or a C16-C20 diacid, optionally via a DD1 spacer;
  • R21 comprises (C1-C4 alkyl)NH 2 covalently linked to a C16-C20 fatty acid, C16-C20 phosphonic fatty acid, or a C16-C20 diacid, optionally via a DD2 spacer;
  • R4, R 8 R24 and R28 are each D;
  • R3 and R23 are each CD3; wherein said DD1 spacer and DD2 spacer are independently -[COCH 2 (OCH 2 CH 2 )k-NH] q -(gamma glutamic acid) p , wherein k is 2, q is 1 or 2 and p is 0 or 1 , optionally wherein k is 2 and q is 2 and p is 1.
  • the prodrug derivative of any one of embodiments 42-44 is provided wherein said DD1 spacer and DD2 spacer are each -[COCH 2 (OCH 2 CH 2 )2- NH]-(gamma glutamic acid)., and the acyl group is a C18-C20 diacid.
  • any one or more of the Pl, P7 or P16 dimers comprises a sequential dipeptide structure (A-B-C-D) of R1 comprises a (C1-C4 alkyl)NH 2 side chain that has been pegylated, via a second spacer, with a straight chain or branched polyethylene glycol chain having a molecular weight ranging from about 20k to about 40k;
  • R21 comprises (C1-C4 alkyl)NH 2 or a (C1-C4 alkyl)NH 2 side chain that has been pegylated, via a second spacer, with a straight chain or branched polyethylene glycol chain having a molecular weight ranging from about 20k to about 40k;
  • R2, and R22 are independently H, or C1-C4 alkyl
  • R4, R 8 , R24 and R28 are independently H, D, or C1-C4 alkyl
  • R3 is CD3, C1-C6 alkyl, or R3 and R4 together with the atoms to which they are attached form a substituted or unsubstituted pyrrolidine, hydroxypyridine or piperdine ring;
  • R2 is CD3, C1-C6 alkyl, or R2 and R24 together with the atoms to which they are attached form a substituted or unsubstituted pyrrolidine, hydroxypyridine or piperdine ring, wherein said second and third spacers are independently -[COCH 2 (OCH 2 CH 2 )k-NH] q -(alanine-triazole), wherein k is 2, and q is 1 or 2, optionally wherein k is 2, or -
  • the prodrug derivative of embodiment 46 is provided wherein R21 comprises a (C1-C4 alkyl)NH 2 side chain that has been pegylated, wherein the pegylation at R2 and R21 is the same or is different.
  • the prodrug derivative of embodiment 46 or 47 is provided wherein said sequential dipeptide structure (A-B-C-D) is covalently linked to i) the amino acid at position 1, relative to SEQ ID NO: 1; ii) the amino acid at position 7, relative to SEQ ID NO: 1 ; iii) the amino acid at position 16, relative to SEQ ID NO: 1 ; or iv) the amino acid at position 1 and 7, relative to SEQ ID NO: 1.
  • the prodrug derivative of any one of embodiments 46-48 is provided wherein R1 and optionally R21 comprises a branched PEG chain construct comprising i) two PEG branches of 10K each ii) two PEG branches of 20K each; iii) four PEG branches of 5K each; or iv) four PEG branches of 10K each.
  • R1 and optionally R21 comprises a branched PEG chain construct comprising i) two PEG branches of 10K each ii) two PEG branches of 20K each; iii) four PEG branches of 5K each; or iv) four PEG branches of 10K each.
  • a prodrug derivative of any one of the peptides of embodiments 46-49 is provided wherein the first amino acid (A) and optionally the third amino acid (C) of said sequential dipeptide element (A-B-C-D) comprises a structure selected from the group consisting of: represents a 20K or 40K PEG,
  • the prodrug derivative of any one of embodiments 16-50 is provided wherein the first amino acid and optionally the third amino acid of said Pl, P7, or Pl 6 dipeptide (A-B) or sequential dipeptide (A-B-C-D) is an amino acid in the D- configuration, optionally wherein said amino acid in the D-configuration is dLys.
  • a prodrug derivative of the peptide of embodiment 11-15 wherein a sequential dipeptide is linked to the N-terminal alpha amine, wherein said a sequential dipeptide “A-B-C-D” comprises the structure of
  • R1 and R 2 I independently comprises -(CH 2 )4NH(COCH 2 (OCH 2 CH 2 ) 2 NH)2-yE- COC18H36CO2H or -(CH 2 ) 4 NH(COCH 2 (OCH 2 CH 2 )2NH)2-yE-COCi8H36PO3H 2 ;
  • R 2 , and R22 are each H;
  • R3 and R23 are independently CH3, or CD3;
  • R21 comprises (C1-C4 alkyl)NH 2 or a (C1-C4 alkyl)NH 2 side chain that has been pegylated, via a second spacer, with a straight chain or branched polyethylene glycol chain having a molecular weight ranging from about 20k to about 40k;
  • R23 is CD3, or CH3, wherein said second and third spacers are independently -[COCH 2 (OCH 2 CH 2 )k-NH] q -(alanine-triazole), wherein k is 2, and q is 1 or 2, optionally wherein k is 2, or -[COCH 2 (OCH 2 CH 2 )k-NH] q -(cysteine-S-S), wherein k is 2, and q is 1 or 2, optionally wherein k is 2, optionally wherein the first and third amino acid of the sequential dipeptide are in the D-stereoisomer configuration.
  • a pharmaceutical composition comprising the peptide of any one of embodiments 1 to 53 and a pharmaceutically acceptable carrier or excipient.
  • a kit comprising a pharmaceutical composition of embodiment 55 and a device for administering said pharmaceutical composition to the patient, optionally wherein the device comprises a syringe comprising the pharmaceutical composition.
  • a method of reducing weight gain or inducing weight loss in a subject wherein a peptide of any one of embodiments 1-15, or a prodrug derivative of any one of embodiments 16-54, or a pharmaceutical composition of embodiment 55 is administered to a subject in need thereof, in an amount effective to reduce weight gain or induce weight loss.
  • the pharmaceutical composition is administered by inhalation.
  • the pharmaceutical composition is administered orally.
  • a method of diabetes in a subject wherein a peptide of any one of embodiments 1-15, or a prodrug derivative of any one of embodiments 16-54, or a pharmaceutical composition of embodiment 54 is administered to a patient in need thereof in an amount effective to lower blood glucose levels.
  • MBX4062 was assembled on 0.1 mmol Rink amide ChemMatrix® resin using an ABI-433A peptide synthesizer and Fmoc/Oxyma/DIC coupling protocols.
  • Fmoc-Lys(Mtt)- OH was used for K 20 .
  • Fmoc-aMePhe-OH was used for aMeF 6 .
  • Boc-Tyr(tBu)-OH was employed to introduce the N-terminal Tyr. Mtt group was removed with HFIP/DCM and the resultant free amine was used for additional extension.
  • This amine was coupled sequentially with two repeat additions of Fmoc-NH-PEGz-CHzCOOH, followed by Fmoc-Glu-OtBu, and finally 20-(tert-Butoxy)-20-oxoicosanoic acid.
  • the peptide was chemically removed from the synthetic resin by treatment with a TFA solution containing 2.5% T1S, 2.5% 2- mercaptoethanol, 2.5 % anisole, and 2.5% H 2 O at room temperature with gentle agitation for 2 hours. The resin was removed by filtration, and the peptide precipitated by addition of cold ether. The peptide precipitate was collected by centrifugation and washed with cold ether.
  • the impure peptide was subjected to purification by preparative reverse-phase HPLC column (Kinetex® 5 pm C8 100 A LC Column 250 X 21.2 mm, 10-50 % aqueous ACN (0.1% TFA), at a flow rate of 15 mL/min).
  • the pure peptide was assessed by analytical LCMS and pooled fractions were lyophilized to provide the final product as a white fluffy solid.
  • Fmoc-Thr-OH was used for Thr 7 .
  • Fmoc-Sar-OH and Boc-dK(Fmoc)-OH were added.
  • Two fatty acid linkers were simultaneously coupled after deprotection of Mtt group and Fmoc group.
  • Fmoc-aMePhe was coupled to the free hydroxyl group of T7 with DIC/DMAP. Further extension of peptide chain as was reported in preparation of MBX 4062 completed the synthesis.
  • Fmoc-Lys(Alloc)-OH was used for Lys 16 .
  • Fmoc-Sar-OH and Boc-dK(Fmoc)-OH were introduced.
  • HFIP/DCM followed by piperdine/DMF provided three free amine groups.
  • Three identical fatty acids with linkers were introduced as previously described in synthesis of MBX 4062.
  • Boc-dK(Fmoc)-OH, Fmoc-dLys(Mtt)-OH, and Fmoc-Lys(Mtt)-OH were used for dLys -3 , dLys’ 1 and Lys 20 .
  • HFIP/DCM Treatment followed by piperdine/DMF treatment provided three free amine groups, to which three identical fatty acids with linkers were introduced as previously described in synthesis of MBX 4062.
  • 19-(Bis(benzyloxy)phosphoryl)nonadecanoic acid was used instead of 20-(tert-Butoxy)-20-oxoicosanoic acid.
  • the cleavage was carried out in a TFA solution containing 5% 12 N HC1, 4 % TIS, and 1 % anisole at room temperature with gentle agitation for 3 hours.
  • Fmoc-Lys(Fmoc)-OH was coupled sequentially to the side chain free amine to generate four amine groups in a branched manner.
  • the initial lysine coupling generated two amines to which the subsequent lysine coupling generates four amines after treatment with 20 % piperidine/DMF.
  • Each of these four amine groups were coupled sequentially with two repeat additions of ollowed by Fmoc-Cys(Trt)-OH, and finally acetic anhydride.
  • the side chain of K 20 was modified as mentioned before.
  • Peptide prodrugs were dissolved in PBS buffer and adjusted to obtain a pH of 7.4. The resulting solution was incubated at 37 °C. Aliquots were taken at designed time points and analyzed by LC-MS. The analysis was performed using an Agilent 1260 Infinity instrument with Phenomenex Kinetex C8 2.6p 100A (75x4.6 mm) column. Flow rate of ImL/min and a gradient of 10% - 80% acetonitrile in water, with 0.1% trifluoroacetic acid over 10 min. Data was collected using absorption at 214 nm. Positive mode MS data were obtained with an Agilent 6120 Quadrupole LC/MS. The concentration of prodrug and drug were determined by their relative peak areas.
  • HEK293 cells co-transfected with the human or mouse GLP- 1 or GIP receptors and a luciferase gene linked to a cAMP inducible responsive element were employed for the bioassay.
  • the cells were serum-deprived by culturing 16 hours in Dulbecco Minimum Essential Medium (Gibco, Life Technologies, Grand Island, NY) supplemented with 0.3% FetalClone III (HyClone, Logan, UT) and then incubated with serial dilutions of the peptide analogs or prodrugs for 5 hours at 37° C., 5% CO2 in 96-well “Costar 3610” Assay plates (Coming, Kennebunk, ME). At the end of the incubation, 50 pL of Steady-Lite Plus luminescence substrate reagent (PerkinElmer, Waltham, MA) were added to each well.
  • Dulbecco Minimum Essential Medium Gibco, Life Technologies, Grand Island, NY
  • FetalClone III HyClone, Logan, UT
  • the plate was shaken briefly at 600 rpm, incubated for four minutes and light output was measured on an EnSpire Alpha Multi-mode Plate Reader (PerkinElmer, Waltham, MA).
  • the effective 50% concentrations (EC50) were calculated using Origin 2019b software (OriginLab, Northampton, MA), and the effective concentration 50 (EC50) was determined by sigmoidal fitting. Potency was determined by comparative analysis of relative EC 50 values. Each experiment was repeated at least three times with each sample assayed in duplicate.
  • mice were tested for their in vivo effects in diet induced obese mice (DIO strain C57B16).
  • Groups of eight mice with initial body weight that varied at start of treatment in the 55-65g range were subcutaneously injected with vehicle or test peptides at a specified dose that varied between 1-30 nmol/kg.
  • the mice varied in age from 5 to 12 months and had been on a high fat diet for approximately two months prior to treatment. Body weights and food consumption were typically measured each morning and no less frequently than every other day in repeat dose experimental protocols.
  • mice C57B1/6 mice were obtained from Jackson Laboratories. The mice were single- or group-housed as was approved by and performed according to the guidelines of the Institutional Animal Care and Use Committee of the University of Cincinnati on a 12:12 h light-dark cycle at 22 °C with free access to food and water.
  • Peptide-based drug and prodrug candidates were tested for their in vivo effects in diet induced obese rats (DIO Sprague Dawley strain). Groups of six or rats with initial body weight that varied at start of treatment in the 600-700g range were subcutaneously injected with vehicle or test peptides at a specified dose that varied between 3-30 nmol/kg. The rats varied in age from 6 to 12 months and had been on a high fat diet for approximately two months prior to treatment. Body weights and food consumption were typically measured each morning and no less frequently than every other day in repeat dose experimental protocols.
  • the SD rats were obtained from Harlan Laboratories. They were single housed as approved by and performed according to the guidelines of the Institutional Animal Care and Use Committee of the University of Cincinnati on a 12: 12 h light-dark cycle at 22 °C with free access to food and water.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Biophysics (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Zoology (AREA)
  • Biochemistry (AREA)
  • Toxicology (AREA)
  • General Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Medicinal Chemistry (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Endocrinology (AREA)
  • Peptides Or Proteins (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

L'invention concerne des peptides qui présentent une activité agoniste du récepteur GIP et GLP-1 ainsi qu'un dérivé de promédicament de ceux-ci. L'invention concerne également des compositions pharmaceutiques comprenant de tels peptides de glucagon et des procédés thérapeutiques d'utilisation de tels peptides.
PCT/US2025/010266 2024-01-05 2025-01-03 Co-agonistes gip/glp-1 et leurs promédicaments associés Pending WO2025147633A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US202463618011P 2024-01-05 2024-01-05
US63/618,011 2024-01-05

Publications (2)

Publication Number Publication Date
WO2025147633A2 true WO2025147633A2 (fr) 2025-07-10
WO2025147633A3 WO2025147633A3 (fr) 2025-08-28

Family

ID=96300693

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2025/010266 Pending WO2025147633A2 (fr) 2024-01-05 2025-01-03 Co-agonistes gip/glp-1 et leurs promédicaments associés

Country Status (1)

Country Link
WO (1) WO2025147633A2 (fr)

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105849122B (zh) * 2013-11-06 2021-04-30 西兰制药公司 Gip-glp-1双重激动剂化合物及方法
TW202523681A (zh) * 2018-07-23 2025-06-16 美商美國禮來大藥廠 Gip/glp1共促效劑化合物
CN110684082B (zh) * 2019-10-08 2021-12-10 江苏诺泰澳赛诺生物制药股份有限公司 Gip和glp-1双激动多肽化合物及药学上可接受的盐与用途

Also Published As

Publication number Publication date
WO2025147633A3 (fr) 2025-08-28

Similar Documents

Publication Publication Date Title
TWI735917B (zh) Gip/glp1共促效劑化合物
TWI622596B (zh) 升糖素受體促效劑
US10406207B2 (en) Peptide conjugates of GLP-1 receptor agonists and gastrin and their use
AU2007323035B2 (en) Antidiabetic compounds
EP2694095B1 (fr) Compositions comprenant des analogues du glucagon et leurs procédés de fabrication et d'utilisation
EP2864350B1 (fr) Analogues du glucagon présentant une activité sur le récepteur du gip
EP2864351B1 (fr) Analogues du glucagon présentant une activité sur le récepteur du gip
KR102653376B1 (ko) 신경펩티드 y 수용체의 조절제로서의 사이클릭 펩티드 티로신 티로신 화합물
EP3075385A1 (fr) Promédicaments peptidiques de la superfamille du glucagon à base d'amide
EP2718317A1 (fr) Analogues de polypeptides insulinotropes dépendants du glucose, compositions pharmaceutiques et son utilisation
KR20110040760A (ko) 대사 질환 및 비만 치료용 ｇｉｐ-기초된 혼합형 항진제
CA2836574A1 (fr) Substances pharmaceutiques peptidiques ameliorees pour la resistance a l'insuline
EP1351984A2 (fr) Glp-1 amide
CN112004822B (zh) 胰高血糖素样肽1(glp-1)融合肽偶联的环状肽酪氨酸-酪氨酸缀合物及其用途
CN105963710A (zh) 具有延长的体内功效的生长激素
WO2025147633A2 (fr) Co-agonistes gip/glp-1 et leurs promédicaments associés
WO2025147621A1 (fr) Tri-agonistes du glucagon, du glp-1 et du gip et leurs promédicaments associés
WO2025147628A2 (fr) Agonistes du récepteur double de l'amyline et de la calcitonine
CN115819551A (zh) 一种定点改造的一类glp-1/胰高血糖素/胃泌素受体三重激动剂及其应用
CN116514952B (zh) 一类glp-1类似物及其应用
CN120437280A (zh) 人胰淀素多肽衍生物的治疗用途
HK1169998B (en) Gip receptor-active glucagon compounds
HK1169998A1 (en) Gip receptor-active glucagon compounds

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 25736539

Country of ref document: EP

Kind code of ref document: A2