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WO2019140023A1 - Polythérapie - Google Patents

Polythérapie Download PDF

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Publication number
WO2019140023A1
WO2019140023A1 PCT/US2019/012955 US2019012955W WO2019140023A1 WO 2019140023 A1 WO2019140023 A1 WO 2019140023A1 US 2019012955 W US2019012955 W US 2019012955W WO 2019140023 A1 WO2019140023 A1 WO 2019140023A1
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Prior art keywords
formula
pharmaceutically acceptable
effective amount
acceptable salt
ethoxy
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Inventor
Tamer Coskun
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Eli Lilly and Co
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Eli Lilly and Co
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/2228—Corticotropin releasing factor [CRF] (Urotensin)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/33—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans derived from pro-opiomelanocortin, pro-enkephalin or pro-dynorphin
    • A61K38/34—Melanocyte stimulating hormone [MSH], e.g. alpha- or beta-melanotropin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics

Definitions

  • the disclosure relates to biology and medicine, and more particularly it relates to a combination of a urocortin-2 (UCN2) analog with a melanocortin 4 receptor (MC4R) agonist, as well as to methods of using the same to treat diabetes and chronic kidney disease (CKD).
  • UCN2 urocortin-2
  • M4R melanocortin 4 receptor
  • Type II diabetes is the most common form of diabetes, as it accounts for about 90% of all diabetes. Over 300 million people worldwide are diagnosed with T2D, which is characterized by high blood glucose levels caused by insulin-resistance. The current standard of care for T2D includes diet and exercise as underlying adjunctive therapy along with available oral and injectable glucose lowering drugs. Nonetheless, individuals with T2D still remain whose symptoms are inadequately controlled. An alternative treatment for T2D is needed.
  • CKD is characterized by a progressive loss of kidney function. Individuals having CKD experience over time an increase in albuminuria, proteinuria, serum creatinine, and renal histopathological lesions. It eventually develops into end stage renal disease (ESRD) for many individuals and requires either dialysis or kidney transplant. CKD may be caused by several underlying conditions including, for example, diabetes (i.e., diabetic nephropathy). The current standard of care for kidney diseases includes angiotensin converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs). There remains a need for an alternative treatment for CKD.
  • ACE angiotensin converting enzyme
  • ARBs angiotensin II receptor blockers
  • ETCN2 is a 38-amino acid endogenous peptide (SEQ ID NO: 12). It is one of three known endogenous urocortins (UCN1 and UCN3 being the others) found in mammals and is part of the corticotropin-releasing hormone (CRH; also referred to as corticotropin releasing factor) family. UCN2 also has been associated with a reduction in blood pressure. See, Mackay et al. (2003) Euro. ./. Pharmacol. 469: 111-115 (2003).
  • Obesity is associated with multiple health problems, predisposing obese people to cardiovascular diseases and T2D. Weight reduction reduces the risk of developing T2D in obese people and therefore is recommended by the American Diabetes Association (“ADA”) as a preventive treatment for T2D. Additionally, weight reduction has been shown to mitigate the risk of cardiovascular disease; however, few treatment options for obesity are available today.
  • ADA American Diabetes Association
  • the melanocortin system has been explored as a target for treating obesity due to its dual role in feeding behavior and energy expenditure contributing to body weight control. Five types of MCRs have been identified, and evidence confirms an association between MC4R and energy regulation. For example, MC4R knock-out mouse studies have demonstrated the involvement of MC4R in feeding behavior and energy expenditure.
  • MT-II nonselective melanocortin agonist melanotan-II
  • MC4R receptor agonists including a molecule called“MC4-NN2-0453”, that have been studied as a potential treatment for obesity: Royalty et al. (2014) J. Clin. Pharmacol. 54:394-404; and Conde-Frieboes et al. (2012) J. Med. Chem. 55: 1969-1977.
  • this disclosure provides a new therapy for CKD and T2D, which includes a combination therapy allowing an individual in need thereof to receive benefits not only of UCN2 but also a MC4R agonist.
  • a combination therapy allowing an individual in need thereof to receive benefits not only of UCN2 but also a MC4R agonist.
  • Such a combination of a UCN2 analog with a MC4R agonist is desired to provide treatment for CKD and T2D, which may be more effective than either therapeutic agent alone.
  • this disclosure describes a combination therapy that may be useful in treating diabetes or CKD.
  • the combination therapy includes administering to an individual in need of such treatment an effective amount of a UCN2 analog according to Formula I (or a pharmaceutically acceptable salt of Formula I) as well as administering to the individual an effective amount of a MC4R agonist (or a pharmaceutically acceptable salt thereof).
  • Formula I i.e., the UCN2 analog
  • I at position 1 is chemically modified by either acetylation or methylation at the N-terminus
  • X dd is Q or E
  • K at position 29 is chemically modified through conjugation to an epsilon- amino group of a K side chain with ([2-(2-amino-ethoxy)-ethoxy] -acetyl ) 2 -(yE) 2 -CO- (CH 2 ) Z -C0 2 H and z is 16 or 18 (SEQ ID NO:8).
  • the terminal V optionally may be amidated as a C-terminal primary amide.
  • I at position 1 is modified by methylation at the N- terminus
  • Xbb is L
  • X cc is L
  • Xdd is Q
  • z is 18 in Formula I (such that Formula I takes the form of SEQ ID NO:4).
  • This instance of Formula I can be combined with a MC4R agonist.
  • pharmaceutically acceptable salts of Formula I and/or the MC4R agonist may be used.
  • I at position 1 is modified by methylation at the N- terminus
  • Xbb is T
  • X cc is I
  • Xdd is E
  • z is 18 in Formula I (such that Formula I takes the form of SEQ ID NO:7).
  • This instance of Formula I can be combined with a MC4R agonist.
  • pharmaceutically acceptable salts of Formula I and/or the MC4R agonist may be used.
  • the MC4R agonist is MC4-NN2-0453, which is a known compound and which may be made according to Royalty et al. (2014), supra ; and Conde- Frieboes et al. (2012), supra.
  • the structure of MC4-NN2-0453 is as shown below: l6-(tetrazol-5-yl)hexadecanoyl-Oeg-Gly-Ser-Gln-His-
  • the combination therapy including an effective amount of a UCN2 analog according to Formula I or a pharmaceutically acceptable salt of Formula I and an effective amount of a MC4R agonist, such as MC4-NN2-0453, or a pharmaceutically acceptable salt thereof for treating CKD and/or diabetes.
  • the combination therapy is used to treat diabetes, especially T2D.
  • Such a combination therapy may be combined with diet and exercise.
  • the combination therapy is used to treat CKD that may be caused by diabetic nephropathy.
  • the combination therapy and methods involve administering a UCN2 analog of Formula I and administering a MC4R agonist, such as MC4-NN2-0453, or pharmaceutically acceptable salts thereof, which may be accomplished by subcutaneously administering one or both compounds.
  • a MC4R agonist such as MC4-NN2-0453, or pharmaceutically acceptable salts thereof
  • Also provided herein is a method of treating CKD or diabetes (including T2D), where the method includes at least a step of administering to an individual in need thereof, an effective amount of a UCN2 analog of Formula I or pharmaceutically acceptable salts thereof including, for example, compounds of SEQ ID NO:4 or SEQ ID NO:7 in combination with an effective amount of a MC4R agonist, such as MC4-NN2-0453, or pharmaceutically acceptable salts thereof.
  • the methods also can include administering an effective amount of one or more additional therapeutic agents.
  • a pharmaceutical composition including (i) an effective amount of a UCN2 analog according to Formula I or a pharmaceutically acceptable salt of Formula I, and (ii) an effective amount of a MC4R agonist, such as MC4-NN2-0453, or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical composition also can include (iii) a pharmaceutically acceptable carrier, diluent or excipient and/or (iv) an additional therapeutic agent.
  • kits for treating CKD or diabetes including T2D including (i) an effective amount of a UCN2 analog according to Formula I or a pharmaceutically acceptable salt thereof, and (ii) an effective amount of a MC4R agonist, such as MC4-NN2-0453, or a pharmaceutically acceptable salt thereof.
  • UCN2 analog of Formula I or a pharmaceutically acceptable salt thereof for use in simultaneous, separate or sequential combination with a MC4R agonist, such as MC4-NN2-0453, or a pharmaceutically acceptable salt thereof for use in treating CKD or diabetes (including T2D).
  • a MC4R agonist such as MC4-NN2-0453
  • a pharmaceutically acceptable salt thereof for use in treating CKD or diabetes (including T2D).
  • Also provided herein is method of treating CKD or diabetes (including T2D), where the method includes at least a step of administering to an individual in need thereof an effective amount of a UCN2 analog of Formula I or a pharmaceutically acceptable salt thereof and an effective amount of a MC4R agonist, such as MC4-NN2-0453, or a pharmaceutically acceptable salt thereof.
  • a MC4R agonist such as MC4-NN2-0453, or a pharmaceutically acceptable salt thereof.
  • the UCN2 analog of Formula I and the MC4R agonist may be subcutaneously administered.
  • a method of treating T2D includes at least a step of administering to an individual in need thereof an effective amount of a UCN2 analog of Formula I or a pharmaceutically acceptable salt thereof, in combination with an effective amount of a MC4R agonist, such as MC4-NN2-0453, or a pharmaceutically acceptable salt thereof.
  • a UCN2 analog of Formula I or a pharmaceutically acceptable salt thereof in combination with an effective amount of a MC4R agonist, such as MC4-NN2-0453, or a pharmaceutically acceptable salt thereof.
  • a MC4R agonist such as MC4-NN2-0453
  • Such a method may be combined with diet and exercise and/or may be combined with additional therapeutic agents.
  • the UCN2 analog of Formula I and the MC4R agonist may be subcutaneously administered.
  • UCN2 analog of Formula I or a pharmaceutically acceptable salt thereof for use in simultaneous, separate or sequential combination with a MC4R agonist, such as MC4-NN2-0453, or a pharmaceutically acceptable salt thereof for treating CKD or diabetes (including T2D) and/or for preventing progression of diabetes into CKD.
  • a MC4R agonist such as MC4-NN2-0453
  • a pharmaceutically acceptable salt thereof for treating CKD or diabetes (including T2D) and/or for preventing progression of diabetes into CKD.
  • UCN2 analog of SEQ ID NO:4 or SEQ ID NO:7 or a pharmaceutically acceptable salt thereof for use in simultaneous, separate or sequential combination with a MC4R agonist, such as MC4-NN2-0453, or a pharmaceutically acceptable salt thereof for treating CKD or diabetes (including T2D).
  • a compound of Formula I or a pharmaceutically acceptable salt thereof for manufacturing a medicament for treating CKD or diabetes (including T2D), where the medicament can be administered simultaneously, separately or sequentially with a MC4R agonist, such as MC4-NN2-0453, or a pharmaceutically acceptable salt thereof.
  • a MC4R agonist such as MC4-NN2-0453, or a pharmaceutically acceptable salt thereof.
  • the UCN2 analog of Formula I is SEQ ID NO:4 or SEQ ID NO: 7 or a pharmaceutically acceptable salt thereof.
  • a UCN2 analog of Formula I or a pharmaceutically acceptable salt thereof in combination with an effective amount of a MC4R agonist, such as MC4-NN2-0453, or a pharmaceutically acceptable salt thereof for use in therapy, in particular, for treating CKD or diabetes (including T2D) and/or for preventing progression of diabetes into CKD.
  • a MC4R agonist such as MC4-NN2-0453
  • a pharmaceutically acceptable salt thereof for use in therapy, in particular, for treating CKD or diabetes (including T2D) and/or for preventing progression of diabetes into CKD.
  • treating CKD and/or treating diabetes includes preventing progression of diabetes into CKD.
  • MC4-NN2-0453 may be made using known techniques, including the techniques and methods outlined in the papers cited above. In some instances, MC4-NN2-0453 may be made into a pharmaceutically acceptable salt.
  • MC4-NN2-0453 in combination with any of the analogs that fit within the scope of Formula I.
  • MC4-NN2-0453 is used in combination with the UCN2 analog of SEQ ID NO:4.
  • MC4-NN2- 0453 is used in combination with the UCN2 analog of SEQ ID NO:7.
  • UCN2 analog of Formula I co- formulated with MC4-NN2-0453.
  • the UCN2 analog of Formula I is administered simultaneously, separately or sequentially with MC4-NN2-0453 compound.
  • the analogs of Formula I can be synthesized using standard manual or automated solid-phase synthesis procedures.
  • Automated peptide synthesizers are commercially available from, for example, Applied Biosystems (Foster City, CA) and Protein Technologies Inc. (Tucson, AZ). Reagents for solid-phase synthesis are readily available from commercial sources. Solid-phase synthesizers can be used according to the manufacturer’s instructions for blocking interfering groups, protecting amino acids during reaction, coupling, deprotecting, and capping of unreacted amino acids.
  • an N-a-carbamoyl protected amino acid and the N-terminal amino acid on the growing peptide chain attached to a resin are coupled at room temperature in an inert solvent such as dimethylformamide, N-methylpyrrolidone or methylene chloride in the presence of coupling agents such as diisopropyl -carbodiimide and l-hydroxybenzotri azole.
  • the Na-carbamoyl protecting group is removed from the resulting peptide resin using a reagent such as trifluoroacetic acid (TFA) or piperidine, and the coupling reaction is repeated with the next desired Na- protected amino acid to be added to the peptide chain.
  • TFA trifluoroacetic acid
  • Suitable amine protecting groups are well known in the art and are described in, for example, Green & Wuts,“Protecting Groups in Organic Synthesis,” (John Wiley & Sons, 1991). The most commonly used examples include tBoc and fluorenylmethoxycarbonyl (Fmoc). After completion of synthesis, peptides are cleaved from the solid-phase support with simultaneous side chain deprotection using standard treatment methods under acidic conditions.
  • peptide chain of the compounds of Formula I can be synthesized with a C-terminal carboxamide.
  • resins incorporating Rink amide MBHA or Rink amide AM linkers can be used with Fmoc synthesis, while MBHA resin can be used with tBoc synthesis.
  • Crude peptides can be purified using RP-HPLC on C8 or C18 columns using water-acetonitrile gradients in about 0.05% to about 0.1% TFA. Peptide purity can be verified by analytical RP-HPLC, and peptide identity can be verified by mass spectrometry. Peptides can be solubilized in aqueous buffers over a wide pH range.
  • the analogs of Formula I and the MC4R agonist as described herein can be formulated as pharmaceutical compositions administered by any route that makes the compound bioavailable.
  • the route of administration may be varied in any way, limited by the physical properties of the therapeutic compounds and the convenience of the individual and the caregiver.
  • the analogs of Formulas I and the MC4R agonist are for parenteral administration, such as intravenous or subcutaneous administration.
  • Other embodiments may be designed in which one or more of such compounds (or pharmaceutically acceptable salts), is for oral, parenteral or transdermal administration, including intravenous or subcutaneous administration.
  • Such pharmaceutical compositions and processes for preparing same are well known in the art. (See, e.g., Remington: The Science and Practice of Pharmacy (Troy, ed., 21 st Ed., Lippincott, Williams & Wilkins, 2006).
  • the analogs of Formula I utilize a fatty acid of the formula C0-(CH 2 ) Z -C0 2 H, where z is 16 or 18 that is chemically conjugated to an epsilon-amino group of a lysine side chain either by a direct bond or by a linker.
  • These acids are“diacids” in that they have a carboxyl group on each end, where one end of the carboxyl is attached via an amide bond to a gE residue.
  • the fatty acid suitable for use herein can be saturated or unsaturated.
  • saturated fatty acids that are suitable for the compounds and uses thereof disclosed herein include octadecanedioic acid (Ci 8 diacid) or eicosanedioic acid (C20 diacid).
  • the fatty acid can be a saturated CTx diacid or a saturated C20 diacid as well as branched and substituted derivatives thereof.
  • the length and composition of the fatty acid impacts the half-life of the compound, the potency of the compound in in vivo animal models, and also impacts the solubility and stability of the compound. Conjugation of the ETCN2 analogs defined herein to a C18-C20 saturated fatty diacid results in compounds that exhibit desirable half-life, desirable potency in in vivo animal models, and also possess desired solubility and stability characteristics.
  • the analogs of Formula I and the MC4R agonist may react with any of a number of inorganic and organic acids to form pharmaceutically acceptable acid addition salts.
  • Pharmaceutically acceptable salts and common methodology for preparing them are well known in the art. See , e.g., Stahl el al. Handbook of Pharmaceutical Salts: Properties, Selection and ETse, 2 nd Revised Edition (Wiley-VCH, 2011); Berge et al. (1977) ./. Pharma Sci. 66: 1-19.
  • Exemplary pharmaceutically acceptable salt for use herein include trifluoroacetate salts, acetate salts and hydrochloride salts among others.
  • the analogs of Formula I or the MC4R agonist may be administered by a clinician physician or self-administered using an injection. It is understood that the gauge size and amount of injection volume can be readily determined by one of skill in the art. In some instances, the amount of injection volume is ⁇ about 2 ml, especially ⁇ about 1 ml. In some instances, the needle gauge is > about 27 G, especially > about 29 G.
  • the analogs of Formula I or the MC4R agonist are generally effective over a wide dosage range.
  • dosages per day normally fall within a range of about 0.01 to about 50 mg/kg of body weight.
  • dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be employed with acceptable side effects, and therefore the above dosage range is not intended to limit the scope of the compositions and methods.
  • the disclosure also encompasses processes useful for synthesizing analogs of Formula I or the MC4R agonist, or a pharmaceutically acceptable salt thereof.
  • the intermediates and compounds herein may be prepared by a variety of processes known in the art including via both chemical synthesis and recombinant technology. For example, the process using chemical synthesis is illustrated in the Examples below. The specific synthetic steps for each of the routes described may be combined in different ways to prepare analogs of Formula I or salts thereof.
  • the reagents and starting materials are readily available to one of skill in the art. It is understood that the Examples are not intended to be limiting to the scope of the compositions and methods in any way.
  • “about” means within a statistically meaningful range of a value or values such as, for example, a stated concentration, length, molecular weight, pH, sequence identity, time frame, temperature, volume, etc. Such a value or range can be within an order of magnitude typically within 20%, more typically within 10%, and even more typically within 5% of a given value or range. The allowable variation encompassed by“about” will depend upon the particular system under study, and can be readily appreciated by one of skill in the art.
  • “Aib” means alpha amino isobutyric acid.
  • AETC means area under the curve.
  • average molecular weight means an average of the molecular weight of the different oligomer size components with a very narrow distribution and is determined by mass spectrometry techniques.
  • ECso means a concentration of compound that results in 50% activation of the assay endpoint, e.g., cAMP.
  • ED50 means a concentration of compound that results in a 50% response in the in vivo assay endpoint, for example, plasma or blood glucose.
  • “effective amount” means an amount or dose of the compound of Formula I, or a pharmaceutically acceptable salt thereof, and to an amount or dose of a compound of Formula II administered to the patient, that provides the desired effect in the patient under diagnosis or treatment. It is understood that the combination therapy of the present invention is carried out by administering a compound of Formula I, or a pharmaceutically acceptable salt thereof, together with the compound of Formula II (or a pharmaceutically acceptable salt thereof) in any manner which provides effective levels of the compound of Formula I (or a pharmaceutically acceptable salt thereof) and the compound of Formula II (or a pharmaceutically acceptable salt) in the body.
  • an effective amount can be readily determined by the attending clinician, as one skilled in the art, by the use of known techniques and by observing results obtained under analogous circumstances. In determining the effective amount for an individual, a number of factors are considered by the attending clinician, including, but not limited to the size, age and general health of the individual; the specific disease or disorder involved; the degree of or involvement or the severity of the disease or disorder; the response of the individual; the particular compound administered; the mode/route of administration; the bioavailability characteristics of the preparation administered; the dose regimen selected; the use of concomitant medication; and other relevant circumstances.
  • fatty acid means a carboxylic acid with either 18 or 20 total carbon atoms.
  • “in combination with” or“in combination” means administration of the compound of Formula I (or pharmaceutically acceptable salt), with a MC4R agonist (or pharmaceutically acceptable salt), simultaneously, or sequentially in any order, or any combination thereof.
  • the two compounds may be administered either as part of the same pharmaceutical composition or in separate pharmaceutical compositions.
  • the compound of Formula I (or pharmaceutically acceptable salt) can be administered prior to, at the same time as, or subsequent to administration of the MC4R agonist (or pharmaceutically acceptable salt),, or in some combination thereof.
  • the MC4R agonist (or pharmaceutically acceptable salt) can be administered prior to, at the same time as, or subsequent to, each administration of the compound of Formula I, or some combination thereof, or at different intervals in relation to therapy with the compound of Formula I, or in a single or series of dose(s) prior to, at any time during, or subsequent to the course of treatment with the compound of Formula I.
  • the compound of Formula I can be administered prior to, at the same time as, or subsequent to, each administration of the MC4R agonist, or some combination thereof, or at different intervals in relation to therapy with the MC4R agonist, or in a single or series of dose(s) prior to, at any time during, or subsequent to the course of treatment with the MC4R agonist.
  • the compounds of Formula I or the MC4R agonist or pharmaceutically salts thereof are particularly useful in the methods of treatment, but certain modifications are preferred for such compounds. It will be understood that these preferences are applicable both to the methods of treatment and to the compounds described herein.
  • “individual” means a mammal, such as a mouse, guinea pig, rat, dog, cat, or primate, especially a human.
  • “saturated” means a fatty acid contains no carbon-carbon double or triple bonds.
  • the term“treating” or“to treat” includes prohibiting, restraining, slowing, stopping, or reversing the progression or severity of an existing symptom or disorder.
  • ACR refers to urine albumin/urine creatinine ratio
  • “amu” refers to atomic mass unit
  • “Boc” refers to tert- butoxycarbonyl
  • “cAMP” refers to cyclic adenosine monophosphate
  • “DMSO” refers to dimethyl sulfoxide
  • “EIA/RIA” refers to enzyme immunoassay/radioimmunoassay
  • “hr” refers to hour
  • HTRF refers to homogenous time-resolved fluorescent
  • “i.v” refers to intravenous
  • “kDa” refers to kilodaltons
  • “LC-MS” refers to liquid chromatography-mass spectrometry
  • “MS” refers to mass spectrometry
  • “OtBu” refers to O-tert-butyl
  • “Pbf” refers to N -2,2,4,6,7-pentamethyldihydrobenzofur
  • IVX bb SLDVPIGLLQILXccEQEKQEKEKQQAKTNAX dd lLAQV-NHi where I at position 1 is modified at the N-terminus by acetylation; X bb is L, X cc is L, X dd is Q, and K at position 29 is chemically modified through conjugation to an epsilon- amino group of a K side chain with ([2-(2-amino-ethoxy)-ethoxy]-acetyl) 2 -(yE) 2 -CO- (CH 2 )i 6 -C0 2 H; and the C-terminal amino acid is amidated as a C-terminal primary amide (SEQ ID NO: 1). The structure of this sequence is shown below.
  • the structure of this sequence contains the standard single letter amino acid code with exception of residues I at position 1 and K at position 29, where the structures of these amino acid residues have been expanded.
  • the peptide according to SEQ ID NO: l is generated by solid-phase peptide synthesis using a Fmoc/t-Bu strategy carried out on a Symphony Automated Peptide Synthesizer (PTI Protein Technologies Inc.; Arlington, A Z) starting from RAPP AM -Rink Amide Resin (H40023 Polystyrene AM RAM, Rapp Polymere GmbH) and with couplings using 6 equivalents of amino acid activated with diisopropylcarbodiimide (DIC) and Oxyma pure (1 : 1 : 1 molar ratio) in dimethylformamide (DMF) for 3 h at 25°C.
  • DIC diisopropylcarbodiimide
  • DMF dimethylformamide
  • the Alloc protecting group present in the K at position 29 is removed using catalytic amounts of Pd(PPh 3 )4 in the presence of PhSiFl ⁇ , as a scavenger. Additional coupling/deprotection cycles is conducted using a Fmoc/t-Bu strategy to extend the K at position 29 side chain involved Fmoc-NH-PEG2-CH 2 COOH (ChemPep Catalog#280102), Fmoc-Glu(OH)-OtBu (ChemPep Catalog# 100703) and HOOC-(CH 2 )i 6 -COOtBu. In all couplings, 3 equivalents of the building block are used with PyBOP (3 equiv) and DIEA (6 equiv) in DMF for 4h at 25°C.
  • Crude peptide is purified to > 99% purity (15-20% purified yield) by reversed-phase HPLC chromatography with water / acetonitrile (containing 0.1% v/v TFA) gradient on a Phenyl hexyl column (phenomenex, 5 micron, 100A), where suitable fractions are pooled and lyophilized.
  • the structure of this sequence contains the standard single letter amino acid code with exception of residues I at position 1 and K at position 29 where the structures of these amino acid residues have been expanded.
  • the peptide according to SEQ ID NO:2 is synthesized similarly as described above in Example 1.
  • HOOC-(CH2)i8-COOtBu is incorporated using 3 equivalents of the building block with PyBOP (3 equiv) and DIEA (6 equiv) in DMF for 4 h at 25°C.
  • the structure of this sequence contains the standard single letter amino acid code with exception of residues N-methyl isoleucine at position 1 and K at position 29, where the structures of these amino acid residues have been expanded.
  • I at position 1 is modified at the N-terminus by methylation
  • X bb is L
  • X cc is L
  • X dd is Q
  • K at position 29 is chemically modified through conjugation to an epsilon-amino group of a K side chain with ([2-(2-amino-ethoxy)-ethoxy]-acetyl) 2 -(yE) 2 - C0-(CH 2 )i 8 -C0 2 H; and the C-terminal amino acid is amidated as a C-terminal primary amide (SEQ ID NO:4).
  • SEQ ID NO:4 The structure of this sequence is shown below.
  • the structure of this sequence contains the standard single letter amino acid code with exception of residues N-methyl isoleucine at position 1 and K at position 29, where the structures of these amino acid residues have been expanded.
  • the compound according to SEQ ID NO:4 is synthesized similarly as described above for Example 1.
  • the N-terminal residue (N-methyl isoleucine at position 1) is incorporated as Boc-NMelle-OH using 6 equivalents of the building block with PyBOP (6 equiv) and DIEA (12 equiv) in DMF-DCM (1 : 1, v/v) for 15 h at 25°C.
  • HOOC-(CH 2 )i 8 - COOtBu is incorporated using 3 equivalents of the building block with PyBOP (3 equiv) and DIEA (6 equiv) in DMF for 4 h at 25°C.
  • IVX bb SLDVPIGLLQILX cc EQEKQEKEKQQAKTNAX dd ILAQV-NH 2 where I at position 1 is modified at the N-terminus by methylation, X bb is T, X cc is L, X dd is E, and K at position 29 is chemically modified through conjugation to an epsilon- amino group of a K side chain with ([2-(2-amino-ethoxy)-ethoxy]-acetyl) 2 -(yE) 2 -CO- (CH 2 )i 8 -C0 2 H; and the C-terminal amino acid is amidated as a C-terminal primary amide (SEQ ID NO:5).
  • SEQ ID NO:5 The structure of this sequence is shown below.
  • the structure of this sequence contains the standard single letter amino acid code with exception of residues N-methyl isoleucine at position 1, and K at position 29 where the structures of these amino acid residues have been expanded.
  • IVX bb SLDVPIGLLQILXccEQEKQEKEKQQAKTNAX dd lLAQV-NHi where I at position 1 is modified at the N-terminus by methylation, X bb is L, X cc is L, X dd is E, and K at position 29 is chemically modified through conjugation to an epsilon- amino group of a K side chain with ([2-(2-amino-ethoxy)-ethoxy]-acetyl) 2 -(yE) 2 -CO- (CH 2 )i 8 -C0 2 H; and the C-terminal amino acid is amidated as a C-terminal primary amide (SEQ ID NO:6).
  • SEQ ID NO:6 The structure of this sequence is shown below.
  • this compound contains the standard single letter amino acid code with exception of residues N-methyl isoleucine at position 1 and K at position 29 where the structures of these amino acid residues have been expanded.
  • IVX bb SLDVPIGLLQILXccEQEKQEKEKQQAKTNAX dd lLAQV-NHi where I at position 1 is modified at the N-terminus by methylation, X bb is T, X cc is I, X dd is E, and K at position 29 is chemically modified through conjugation to an epsilon- amino group of a K side chain with ([2-(2-amino-ethoxy)-ethoxy]-acetyl) 2 -(yE) 2 -CO- (CH 2 )i 8 -C0 2 H; and the C-terminal amino acid is amidated as a C-terminal primary amide (SEQ ID NO:7).
  • SEQ ID NO:7 The structure of this sequence is shown below.
  • the structure of this sequence contains the standard single letter amino acid code with exception of residues N-methyl isoleucine at position 1 and K at position 29, where the structures of these amino acid residues have been expanded.
  • a convergent synthesis also may be used.
  • an acylated K side chain is constructed and/or obtained.
  • This acylated K side chain fragment may have the acid fragments protected orthogonally as t-butyl esters or other protecting groups commonly known in peptide synthesis. It is believed that such a method of synthesis may produce the acylated side chain in high purity, > 98%, which may reduce the downstream chromatography requirements, potentially leading to improved purity and increased process efficiency.
  • the acylated K component i.e., the fatty acid side chain having the amino-ethoxy moeities, etc.
  • the acylated K component typically is installed at the end of the synthesis, and this can create high levels of process impurities such as, but not limited to impurities have greater or fewer numbers of amino-ethoxy moieties which can be problematic to remove.
  • Using the convergent synthesis approach may de-risk an all linear synthetic build strategy, where a single mistake can result in a total loss.
  • using a convergent synthesis approach may improve supply chain flexibility with comparable resourcing requirements to a standard all linear build.
  • a convergent synthesis approach also may be a means of lowering COPS (cost of product sold) and further improving robustness.
  • Another benefit may be that the N-terminus N-methyl isoleucine residue frequently is a difficult coupling for a large peptide. Incorporation of N-methyl isoleucine onto a smaller fragment may be potentially a good means of de-risking this coupling issue.
  • this“fragment” will include the K at position 29 (and its accompanying side chain) along with the final 9 residues (leading up to the C-terminus).
  • this“fragment” may be the primary parent fragment produced on Rink Amide or Sieber Amide resin.
  • Another retrosynthetic disconnection may be between G at position 10 and the L at position 11. Making a fragment of these sequences may ensure that such a sequence has no (or a lower) propensity for racemization.
  • the third fragment of 18 amino acids (e.g ., from the residue at position 11 to the A at position 28) also could be produced.
  • the 2-CTC resin may be preferred for synthesis of most fragments as the resin can be orthogonally cleaved while leaving peptide protecting groups intact.
  • the 18-amino acid fragment of step 3 could be coupled to the lO-amino acid fragment of step 4, and then this 28-residue construct could be coupled to the fragment of step 2 (having the side chain); alternatively the 18-amino acid fragment of step 3 could be coupled to the added to 10-amino acid fragment of step 2, and then this 28-residue construct could be coupled to the fragment of step 4.
  • each fragment could be produced sequentially or simultaneously.
  • the smaller fragments of the peptides may be easier to purify and sometimes can be isolated in crystalline form which imparts high purity.
  • an error is made in one of the fragment, only that fragment has to be discarded and re-created (rather than having to re create the entire sequence).
  • Other strategic fragment breaks are posssible to further improve purity and efficiency such as but not limited to fragment condensation to produce the 18- clinician amino acid residue.
  • lyophilization may be incorporated as the strategy as a means of potentially de-risking potential physical property issues of the compound.
  • the compound may be constructed by in which it is purified via chromatography. Once purified, the solution may be concentrated and then isolated as a solid (e.g, dry powder) via lyophilization. In other instances, a solid may be obtained and isolated using a precipitation/filtration/drying/humidification procedure.
  • Lyophilization is the most commonly practiced (> 80%) industrial means for production of solid peptide drug products for storage or reconstitution.
  • the primary drawback to precipitation is the extensive material and design space development necessary to assure a robust process.
  • Precipitated compounds also may contain high density particles that tend to agglomerate, and frequently these precipated products may slowly dissolve with standard dissolution assays and/or drug product formulations.
  • high surface area product produced by lyophilization may assure maximized dissolution rates in dissolution assays and/or pharmaceutical formulations.
  • precipitation products also may be used, as this method tends to be less expensive for high volume products.
  • CRHR agonistic activity is measured in a cell-based cAMP assay.
  • Serial dilutions of the test peptides are made in assay buffer containing Hank’s Balanced Salt Solution (HBSS, without phenol red) supplemented with 20 mM HEPES and 0.05% lactalbumin enzymatic hydrolysate (LAH) (“assay buffer”).
  • HBSS Hank’s Balanced Salt Solution
  • LAH lactalbumin enzymatic hydrolysate
  • a one to three dilution of the test peptides is used in both assays.
  • a receptor over-expressing Chinese Hamster Ovary (CHO) cell line is used for the human CRHR2b assay.
  • CHO cells are grown in DMEM supplemented with 10% fetal bovine serum at 37°C under suspension conditions and transiently transfected with cDNA constructs of human CRHR2b (Genbank Accession No.: AF011406.1). Forty-eight hours after the transfection, the cells are centrifuged to remove the culture media and re suspended in fetal bovine serum containing 5% DMSO. They are cryofrozen and stored in vials in liquid nitrogen (20 x 10 6 cells/ml/vial).
  • cells are thawed and re-suspended in cold 30ml culture media supplemented with 20mM HEPES. The cells are then centrifuged to remove the media and washed once with HBSS supplemented with 20mM HEPES. Finally, following the last centrifugation, the cells are resuspended in assay buffer. Thirty thousand cells are used in the human CRHR2b assay for each treatment.
  • a human retinoblastoma cell line Y79 (ATCC #HTB- 18), which expresses endogenous human CRHR1, is used in the human CRHR1 assay.
  • the cells are grown in RPMI 1640 (Hyclone, #SH30255) containing 20% fetal bovine serum and lOmM HEPES, in suspension culture. Cells are centrifuged to remove the culture media and washed once in HBSS supplemented with 20 mM HEPES. The cells are re-suspended in the assay buffer and 20,000 cells are used per treatment in the human CRHR1 assay.
  • the cells are dispensed into Costar 96-well black polystyrene half area EIA/RIA plates (Corning Incorporated, Coming, NY) followed by the addition of the diluted peptides, each at a volume of 20 pL.
  • the agonist induced cAMP levels are detected using a HTRF cAMP Dynamic 2 kit (CisBio, Bedford, MA). After incubation at 37°C for 30 min, the assay is stopped by cell lysis via the addition of 20 pL of d2 -labeled cAMP and followed by 20 pL of cryptate-labeled anti-cAMP antibody, as described by the manufacturer.
  • Cellular cAMP (as a result of agonist stimulation) competes with the d2- labeled cAMP for binding to the antibody.
  • HTRF detection is performed on an Envision plate reader (Perkin Elmer Life and Analytical Sciences, Waltham, MA) by measuring ratiometric emission at 620 and 665 nm after excitation at 320 nm.
  • the data are converted to picomoles of cAMP using a standard curve obtained from the same assay performed with varying concentrations of unlabeled cAMP. Percent of the maximum activation of the cells is calculated using converted picomole cAMP data by comparing to the amount of cAMP produced by 1 pM human ETCN2 for the human CRHR2b or 1 pM human ETCN 1 for the human CRHR1 assay. The data are analyzed using a Curve Fitting Tool to calculate EC50. Numeric values shown below in Table 1 represent the mean of multiple runs (number of runs shown in parentheses) following the mean value
  • This example describes an effect of a long-acting UCN2 analog,“UCN2-X,” in combination with a MC4R agonist on metabolic parameters in DIO mice.
  • UCN2 analogs are proposed as a treatment not only for diabetes but also for metabolic syndrome, a collection of co-morbidities (dyslipidemia, obesity, hepatic steatosis, etc.) that are associated with insulin resistance and diabetes.
  • UCN2-X UCN2-X’s mechanism of inducing body weight loss in combination with a MC4R agonist is investigated.
  • “UCN2-X” refers to the compound of Example 7 above
  • “MC4R agonist” refers to MC4-NN2-0453.
  • the DIO model represents a pre-diabetic state that is more sensitive to insulin. These animals, although not diabetic, display insulin resistance, dyslipidemia, and hepatic steatosis, all characteristics of metabolic syndrome, after being placed on a high fat (60% Kcal from fat) diet for 12 weeks (Surwit et al. (1988) Diabetes 37: 1163-1167).
  • the purpose of this example thereof is to assess the effects of a UCN2 compound of Formula I alone and in combination with a MC4R agonist on fasting glucose, fasting insulin, weight loss and body composition.
  • C57/BL6 diet-induced obese (DIO) male mice (Taconic; Germantown, NY) weighing 46-53 g are individually housed in a temperature-controlled (24°C) facility with a l2-hour light/dark photoperiod (lights off at 11 :00 AM and lights on at 11 :00 PM), and have free access to a 60% fat diet (D12492) (Teklad; Indianapolis, IN) and water. The study starts after two week acclimatization to the facility.
  • Vehicle 40 mM Tris-HCl Buffer at pH 8.0, 10 ml/kg, s.c.
  • Table 2 shows data corresponding to each of the above measurements. All data is expressed as group mean ⁇ SEM. Data analysis is done with JMP software and statistical analyses are assessed by a one-way ANOVA followed by Dunnett’s or Tukey’s multiple comparison test to compare treatment groups to vehicle group or each other. Cumulative body weight is calculated by subtracting study day -1 BW from the final study day 14 BW. Fat mass and fat free mass are determined by the difference in QNMR values on study days -1 and 14. Fat free mass is determined by subtracting the fat mass from the animal’s body weight taken on study day -1 or 14 respectively.
  • Table 2 Effect of Treatment With UCN2-X, MC4-NN2-0453 or Combination Thereof.
  • Matsuda Index is calculated by the following equation: 10000/(SQRT ((animal’s glucose (mMol/L) time 0 value*animal’s insulin (uU/mL) time 0 value)* (animal’s average Glucose value (mMol/L) *ammal’s average insulin value (uU/mL)))).
  • HOMA-IR is calculated by the following equation: (Animal’s glucose (mMol/L) time 0 value *animaTs insulin (uU/mL) time 0 value)/22.5 [0126]
  • body weight for UCN2-X, MC4-NN2-0453, and the combination of UCN2-X + MC4-NN2-0453 when compared to vehicle, and this effect was driven mainly by a decrease in food intake.
  • body weight change for all 3 groups compared to vehicle, but this effect was most prominent in UCN2-X and UCN2-X + MC4-NN2-0453 groups.
  • a significant difference also is found when comparing the cumulative weight loss of UCN2- X to UCN2-X + MC4-NN2-0453.
  • Glucose AUC values reflect this trend with a value of 26499 ⁇ 2l32 for vehicle, 16179 ⁇ 229 for UCN2-X, 21206 ⁇ 1024 for MC4-NN2-0453, and l5084 ⁇ 534 for the combo group.
  • the combo group shows significant lowering at all time points when compared to vehicle but not beyond what the individual treatments are able to do.
  • HOMA-IR values are significantly lower for UCN2-X (51 ⁇ 4.5), MC4-NN2-0453 (24 ⁇ 2) and combo group (99 ⁇ 10) when compared to control(l5 ⁇ l) and the Matsuda Index values (Table 2) were significantly higher for UCN2-X and UCN2-X+MC4-NN2-0453 groups. A significant difference is found with increased Matsuda Index value of the combo group compared to the UCN2-X group alone.
  • I at position 1 is modified at the N-terminus by acetylation
  • K at position 29 is chemically modified through conjugation to an epsilon-amino group of a K side chain with ([2-(2-amino-ethoxy)-ethoxy]-acetyl) 2 -(YE) 2 -C0-(CH 2 )i 6 -C0 2 H; and the C-terminal amino acid is amidated as a C-terminal primary amide.
  • I at position 1 is modified at the N-terminus by acetylation, and K at position 29 is chemically modified through conjugation to an epsilon-amino group of a K side chain with ([2-(2-amino-ethoxy)-ethoxy]-acetyl) 2 -(yE) 2 -CO-(CH 2 )ix-C0 2 H; anc j the C-terminal amino acid is amidated as a C-terminal primary amide.
  • I at position 1 is modified at the N-terminus by methylation, and K at position 29 is chemically modified through conjugation to an epsilon-amino group of a K side chain with ([2-(2-amino-ethoxy)-ethoxy]-acetyl) 2 -(yE) 2 -CO-(CH 2 )i 6 -C0 2 H; ancj the C-terminal amino acid is amidated as a C-terminal primary amide.
  • I at position 1 is modified at the N-terminus by methylation, and K at position 29 is chemically modified through conjugation to an epsilon-amino group of a K side chain with ([2-(2-amino-ethoxy)-ethoxy]-acetyl) 2 -(yE) 2 -CO-(CH 2 )ix-C0 2 H; ancj the C-terminal amino acid is amidated as a C-terminal primary amide.
  • I at position 1 is modified at the N-terminus by methylation, and K at position 29 is chemically modified through conjugation to an epsilon-amino group of a K side chain with ([2-(2-amino-ethoxy)-ethoxy]-acetyl) 2 -(yE) 2 -CO-(CH 2 )ix-C0 2 H; ancj the C-terminal amino acid is amidated as a C-terminal primary amide.
  • I at position 1 is modified, at the N-terminus, by methylation, and K at position 29 is chemically modified through conjugation to an epsilon-amino group of a K side chain with ([2-(2-amino-ethoxy)-ethoxy]-acetyl) 2 -(yE) 2 -CO-(CH 2 )ix-C0 2 H; ancj the C-terminal amino acid is amidated as a C-terminal primary amide.
  • I at position 1 is chemically modified by either acetylation or methylation at the N-terminus
  • X bb is L or T
  • X cc is L or I
  • X dd is Q or E
  • K at position 29 is chemically modified through conjugation to an epsilon-amino group of a K side chain with

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Abstract

L'invention concerne une polythérapie pour le traitement du diabète ou d'une insuffisance rénale chronique par l'administration à un individu qui a besoin d'un tel traitement d'une quantité efficace d'un composé d'urocortine-2 (ou d'un sel pharmaceutiquement acceptable de celui-ci) avec un agoniste du MC4R (ou un sel pharmaceutiquement acceptable de celui-ci), et des procédés d'utilisation de celle-ci pour traiter le diabète et une insuffisance rénale chronique.
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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008047241A2 (fr) * 2006-10-16 2008-04-24 Conjuchem Biotechnologies Inc. Peptides du facteur libérateur de corticotrophine modifiés et leurs utilisations
WO2018013803A1 (fr) * 2016-07-15 2018-01-18 Eli Lilly And Company Nouveaux analogues d'urocortine-2 modifiés par acides gras pour le traitement du diabète et de maladies rénales chroniques

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008047241A2 (fr) * 2006-10-16 2008-04-24 Conjuchem Biotechnologies Inc. Peptides du facteur libérateur de corticotrophine modifiés et leurs utilisations
WO2018013803A1 (fr) * 2016-07-15 2018-01-18 Eli Lilly And Company Nouveaux analogues d'urocortine-2 modifiés par acides gras pour le traitement du diabète et de maladies rénales chroniques

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BERGE ET AL., J. PHARMA SCI., vol. 66, 1977, pages 1 - 19
CONDE-FRIEBOES ET AL., J. MED. CHEM., vol. 55, 2012, pages 1969 - 1977
GREEN; WUTS: "Protecting Groups in Organic Synthesis", 1991, JOHN WILEY & SONS
JANE E. ROYALTY ET AL: "Investigation of safety, tolerability, pharmacokinetics, and pharmacodynamics of single and multiple doses of a long-acting [alpha]-MSH analog in healthy overweight and obese subjects", JOURNAL OF CLINICAL PHARMACOLOGY., vol. 54, no. 4, 1 April 2014 (2014-04-01), US, pages 394 - 404, XP055522276, ISSN: 0091-2700, DOI: 10.1002/jcph.211 *
MACKAY ET AL., EURO. J. PHARMACOL., vol. 469, 2003, pages 111 - 115
MEI HUA GAO ET AL: "One-time injection of AAV8 encoding urocortin 2 provides long-term resolution of insulin resistance", JCI INSIGHT, vol. 1, no. 15, 22 September 2016 (2016-09-22), XP055410687, DOI: 10.1172/jci.insight.88322 *
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