Human glucagon-like-peptide-1 modulators and their use in the treatment of diabetes and related conditions

Abstract

The present invention provides novel human glucagon-like peptide-1 (GLP-1)-receptor modulators that have biological activity similar or superior to native GLP-1 peptide and thus are useful for the treatment or prevention of diseases or disorders associated with GLP activity. Further, the present invention provides novel, chemically modified peptides that not only stimulate insulin secretion in type II diabetics, but also produce other beneficial insulinotropic responses. These synthetic peptide GLP-1 receptor modulators exhibit increased stability to proteolytic cleavage making them ideal therapeutic candidates for oral or parenteral administration. The peptides of this invention show desirable pharmacokinetic properties and desirable potency in efficacy models of diabetes.

1 . A compound of Formula VIa: 
       
         
           
           
               
               
           
         
       
       wherein P is hydrogen, fluorenylmethyloxycarbonyl (Fmoc) or t-butyloxycarbonyl (t-Boc); wherein R3a is selected from the group consisting of methyl, ethyl and fluoro; wherein R10 is selected from the group consisting of OH and NH2; and wherein R7 is selected from the group consisting of hydrogen and methyl. 
     
     
         2 . A compound of Formula VIIa: 
       
         
           
           
               
               
           
         
       
       wherein P is hydrogen, fluorenylmethoxycarbonyl (Fmoc) or t-butyloxycarbonyl (t-Boc); wherein R6a is methoxy; wherein R10 is selected from the group consisting of OH and NH2; and wherein R7 is selected from the group consisting of hydrogen and methyl. 
     
     
         3 . A method for treating or delaying the progression or onset of diabetes, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, wound healing, insulin resistance, hyperglycemia, hyperinsulinemia, Syndrome X, diabetic complications, elevated blood levels of free fatty acids or glycerol, hyperlipidemia, obesity, hypertriglyceridemia, atherosclerosis or hypertension, which comprises administering to a mammalian species in need of treatment a therapeutically effective amount of a pharmaceutical composition comprising an isolated polypeptide comprising SEQ ID NO:93. 
     
     
         4 . The method of  claim 3 , further comprising the concurrent or sequential administration of a therapeutically effective amount of one or more therapeutic agents selected from the group consisting of an antidiabetic agent, an anti-obesity agent, a anti-hypertensive agent, and an anti-atherosclerotic agent and a lipid-lowering agent. 
     
     
         5 . A method for treating or delaying the progression or onset of diabetes, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, wound healing, insulin resistance, hyperglycemia, hyperinsulinemia, Syndrome X, diabetic complications, elevated blood levels of free fatty acids or glycerol, hyperlipidemia, obesity, hypertriglyceridemia, atherosclerosis or hypertension, which comprises administering to a mammalian species in need of treatment a therapeutically effective amount of a pharmaceutical composition comprising an isolated polypeptide of SEQ ID NO:93. 
     
     
         6 . A method for administering a polypeptide of SEQ ID NO:93, comprising the parenteral administration of a formulation comprising a polypeptide of SEQ ID NO:93. 
     
     
         7 . A method for administering a polypeptide of SEQ ID NO:93, comprising the non-parenteral administration of a formulation comprising a polypeptide of SEQ ID NO:93. 
     
     
         8 . The method of  claim 6 , wherein said parenteral administration is selected from the group consisting of intravenous (IV) bolus injection, IV infusion, subcutaneous administration, intramuscular administration, intranasal administration, buccal administration, pulmonary administration and ophthalmic delivery. 
     
     
         9 . The method of  claim 8 , wherein said administration involves the use of an immediate or sustained release formulation. 
     
     
         10 . The method of  claim 6 , wherein said formulation further comprises a pharmaceutically acceptable excipient selected from the group consisting of a solvent and co-solvent, a solubilizing agent, an emulsifying agent, a thickening agent, a chelating agent, an anti-oxidant, a reducing agent, an antimicrobial preservative, a buffer and pH adjusting agent, a bulking agent, a protectant and tonicity adjustor, and a special additive and said formulation may further comprise an encapsulated delivery system. 
     
     
         11 . A polypeptide comprising a sequence selected from the group consisting of SEQ ID NOs:17, 60, 64, 78, 80, and 90. 
     
     
         12 . A pharmaceutical composition, comprising a polypeptide selected from the group consisting of SEQ ID NOs: 17, 60, 64, 78, 80 and 90 and a pharmaceutically acceptable carrier thereof. 
     
     
         13 . A pharmaceutical combination comprising a polypeptide of  claim 11  and at least one therapeutic agent selected from the group consisting of an antidiabetic agent, an anti-obesity agent, an anti-hypertensive agent, an anti-atherosclerotic agent and a lipid-lowering agent. 
     
     
         14 . The combination of  claim 13  wherein the antidiabetic agent is at least one agent selected from the group consisting of a biguanide, a sulfonyl urea, a glucosidase inhibitor, a peroxisome proliferator-activated receptor (PPAR) γ agonist, a PPAR α/γ dual agonist, an adipocyte lipid binding protein (aP2) inhibitor, a dipeptidyl peptidase 4 (DP4) inhibitor, an insulin sensitizer, a glucagon-like peptide-1 (GLP-1), insulin and a meglitinide. 
     
     
         15 . The combination of  claim 14  wherein the antidiabetic agent is at least one agent selected from the group consisting of metformin, glyburide, glimepiride, glipyride, glipizide, chlorpropamide, gliclazide, acarbose, miglitol, pioglitazone, troglitazone, rosiglitazone, insulin, farglitizar, isaglitazone, reglitizar, muraglitazar, saxagliptin, balaglitazone, (Z)-1,4-bis{4-[(3,5-Dioxo-1,2,4-oxadiazolidin-2-yl)methyl]phenoxy}but-2-ene, rivoglitazone, rafaegron, repaglinide, nateglinide, (S)-2-benzyl-4-oxo-4-(cis-perhydroisoindol-2-yl)butyric acid calcium salt, tesaglitizar, L-phenylalanine, N-[(1Z)-1-methyl-3-oxo-3-phenyl-1-propenyl]-4-[3-(5-methyl-2-phenyl-4-oxazolyl)propyl], 5-[(2,4-dioxo-5-thiazolidinyl)methyl]-2-methoxy-N-[[4-(trifluoromethyl)phenyl]methyl]-benzamide, exenatide, 8-37-glucagon-like peptide I (human)-N-[3-(1H-imidazol-4-yl)-1-oxopropyl]-26-L-arginine-34-[N6-(1-oxooctyl)-L-lysine], and vildagliptin. 
     
     
         16 . The combination of  claim 13  wherein the anti-obesity agent is at least one agent selected from the group consisting of a beta 3 adrenergic agonist, a lipase inhibitor, a serotonin reuptake inhibitor, a dopamine reuptake inhibitor, a serotonin and dopamine reuptake inhibitor, a thyroid receptor beta compound, and an anorectic agent. 
     
     
         17 . The combination of  claim 16  wherein the anti-obesity agent is at least one agent selected from the group consisting of orlistat, cetilistat, rafabregon, N-[4-[2-[[(2S)-3-[(6-amino-3-pyridinyl)oxy]-2-hydroxypropyl]amino]ethyl]phenyl]-4-(1-methylethyl)-benzenesulfonamide, sibutramine, topiramate, axokine, dexamphetamine, phentermine, phenylpropanolamine, rimonabant and mazindol. 
     
     
         18 . The combination of  claim 13  wherein the lipid lowering agent is at least one agent selected from the group consisting of a microsomal triglyceride transfer protein (MTP) inhibitor, cholesterol ester transfer protein, a hydroxy-3-methyl-glutaryl-coenzyme A (HMG CoA) reductase inhibitor, a squalene synthetase inhibitor, a fibric acid derivative, an upregulator of low-density lipoprotein (LDL) receptor activity, a lipoxygenase inhibitor, or an acyl coenzyme A-cholesterol acyltransferase (ACAT) inhibitor. 
     
     
         19 . The combination of  claim 18  wherein the lipid lowering agent is at least one agent selected from the group consisting of pravastatin, lovastatin, simvastatin, atorvastatin, cerivastatin, fluvastatin, nisvastatin, visastatin, fenofibrate, gemfibrozil, clofibrate, avasimibe, N-[2,6-bis(1-methylethyl)phenyl]-2-(tetradecylthio)-acetamide, 3-(13-hydroxy-10-oxotetradecyl)-5,7-dimethoxy-1(3H)-isobenzofuranone, torcetrapib, and (3 alpha,4 alpha,5 alpha)-4-(2-propenylcholestan-3-ol). 
     
     
         20 . A method for treating or delaying the progression or onset of diabetes, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, wound healing, insulin resistance, hyperglycemia, hyperinsulinemia, Syndrome X, diabetic complications, elevated blood levels of free fatty acids or glycerol, hyperlipidemia, obesity, hypertriglyceridemia, atherosclerosis or hypertension, which comprises administering to a mammalian species in need of treatment a therapeutically effective amount of a pharmaceutical composition comprising an isolated polypeptide of  claim 11 . 
     
     
         21 . The method of  claim 20 , further comprising the concurrent or sequential administration of a therapeutically effective amount of one or more therapeutic agents selected from the group consisting of an antidiabetic agent, an anti-obesity agent, a anti-hypertensive agent, and an anti-atherosclerotic agent and a lipid-lowering agent. 
     
     
         22 . A method for treating or delaying the progression or onset of diabetes, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, wound healing, insulin resistance, hyperglycemia, hyperinsulinemia, Syndrome X, diabetic complications, elevated blood levels of free fatty acids or glycerol, hyperlipidemia, obesity, hypertriglyceridemia, atherosclerosis or hypertension, which comprises administering to a mammalian species in need of treatment a therapeutically effective amount of an isolated polypeptide of  claim 11 . 
     
     
         23 . A method for administering a polypeptide of  claim 11 , comprising the parenteral administration of a formulation comprising a polypeptide of  claim 11 . 
     
     
         24 . A method for administering a polypeptide of  claim 11 , comprising the non-parenteral administration of a formulation comprising a polypeptide of  claim 11 . 
     
     
         25 . The method of  claim 23 , wherein said parenteral administration is selected from the group consisting of intravenous (IV) bolus injection, IV infusion, subcutaneous administration, intramuscular administration, intranasal administration, buccal administration, pulmonary administration and ophthalmic delivery. 
     
     
         26 . The method of  claim 25 , wherein said subcutaneous administration involves the use of an immediate or sustained release formulation. 
     
     
         27 . The method of  claim 25 , wherein said intramuscular administration involves the use of an immediate or sustained release formulation. 
     
     
         28 . The method of  claim 23 , wherein said formulation further comprises a pharmaceutically acceptable excipient selected from the group consisting of a solvent and co-solvent, a solubilizing agent, an emulsifying agent, a thickening agent, a chelating agent, an anti-oxidant, a reducing agent, an antimicrobial preservative, a buffer and pH adjusting agent, a bulking agent, a protectant and tonicity adjustor, and a special additive and said formulation may further comprise an encapsulated delivery system.