ABSTRACT
A series of non-steroidal GPBAR1 (TGR5) agonists was developed from a hit in a high-throughput screening campaign. Lead identification efforts produced biphenyl-4-carboxylic acid derivative (R)-22, which displayed a robust secretion of PYY after oral administration in a degree that can be correlated with the unbound plasma concentration. Further optimisation work focusing on reduction of the lipophilicity provided the 1-phenylpiperidine-4-carboxylic acid derivative (R)-29 (RO5527239), which showed an improved secretion of PYY and GLP-1, translating into a significant reduction of postprandial blood glucose excursion in an oral glucose tolerance test in DIO mice.
Subject(s)
Blood Glucose/drug effects , Drug Discovery , Oximes/chemical synthesis , Propane/analogs & derivatives , Receptors, G-Protein-Coupled/agonists , Administration, Oral , Animals , Inhibitory Concentration 50 , Mice , Molecular Structure , Oximes/chemistry , Oximes/pharmacology , Propane/blood , Propane/chemical synthesis , Propane/chemistry , Propane/pharmacologyABSTRACT
BACKGROUND: Somatostatin regulates numerous endocrine processes, including glucose homeostasis. The contribution and effects of the 5 somatostatin receptors are still unclear, in part due to the lack of suitable subtype specific receptor antagonists. We explored the effects of two novel, non-peptidic, orally bioavailable somatostatin receptor subtype 5 antagonists named Compound A and Compound B on glycemia in animal models of type 2 diabetes after an initial in vitro characterization. METHODS AND RESULTS: Compound A led to a dose-dependent decrease in glucose and insulin excursions during an OGTT in Zucker (fa/fa) rats after single treatment by up to 17% and 49%, respectively. Diet-induced obese mice showed after three weeks treatment with compounds A and B a dose-dependent decrease of the glucose excursion of up to 45% and 37%, respectively. In contrast to the acute effect observed in Zucker rats, Compound A showed a dose-dependent insulin increase by up to 72%, whereas body weight, liver triglycerides, ALT and AST were dose-dependently decreased. CONCLUSIONS: SSTR5 antagonists have the potential for short- and long-term improvements of the glucose homeostasis in rodent models of type 2 diabetes. Further work on the mechanism and the relevance for human disease is warranted.
Subject(s)
Blood Glucose/metabolism , Diabetes Mellitus, Experimental/drug therapy , Hypoglycemic Agents/pharmacology , Obesity/drug therapy , Receptors, Somatostatin/antagonists & inhibitors , Animals , Body Weight/drug effects , CHO Cells , Cricetinae , Cricetulus , Diabetes Mellitus, Experimental/blood , Dose-Response Relationship, Drug , Homeostasis/drug effects , Humans , Liver/metabolism , Mice , Obesity/blood , Rats , Rats, Zucker , Receptors, Somatostatin/metabolism , Triglycerides/metabolismABSTRACT
Design, synthesis, and SAR are described for a class of DPP-IV inhibitors based on aminobenzo[a]quinolizines with non-aromatic substituents in the S1 specificity pocket. One representative thereof, carmegliptin (8p), was chosen for clinical development. Its X-ray structure in complex with the enzyme and early efficacy data in animal models of type 2 diabetes are also presented.
Subject(s)
Diabetes Mellitus, Type 2/drug therapy , Dipeptidyl-Peptidase IV Inhibitors , Dipeptidyl-Peptidase IV Inhibitors/chemical synthesis , Drug Design , Hypoglycemic Agents/chemical synthesis , Quinolizines/chemical synthesis , Animals , Clinical Trials, Phase II as Topic , Crystallography, X-Ray , Delayed-Action Preparations , Diabetes Mellitus, Type 2/enzymology , Diabetes Mellitus, Type 2/metabolism , Dipeptidyl Peptidase 4/metabolism , Dipeptidyl-Peptidase IV Inhibitors/administration & dosage , Dipeptidyl-Peptidase IV Inhibitors/therapeutic use , Dogs , Humans , Hypoglycemic Agents/administration & dosage , Hypoglycemic Agents/therapeutic use , Macaca fascicularis , Mice , Quinolizines/administration & dosage , Quinolizines/therapeutic use , Rats , Rats, Wistar , Rats, ZuckerABSTRACT
Synthesis and SAR are described for a structurally distinct class of DPP-IV inhibitors based on aminobenzo[a]quinolizines bearing (hetero-)aromatic substituents in the S1 specificity pocket. The m-(fluoromethyl)-phenyl derivative (S,S,S)-2g possesses the best fit in the S1 pocket. However, (S,S,S)-2i, bearing a more hydrophilic 5-methyl-pyridin-2-yl residue as substituent for the S1 pocket, displays excellent in vivo activity and superior drug-like properties.
