ABSTRACT
The transformation of an aryloxybutanoic acid ultra high-throughput screening (uHTS) hit into a potent and selective series of G-protein coupled receptor 120 (GPR120) agonists is reported. uHTS hit 1 demonstrated an excellent rodent pharmacokinetic profile and selectivity over the related fatty acid receptor GPR40, but only modest GPR120 potency. Optimization of the "left-hand" aryl group led to compound 6, which demonstrated a GPR120 mechanism-based pharmacodynamic effect in a mouse oral glucose tolerance test (oGTT). Further optimization gave rise to the benzofuran propanoic acid series (exemplified by compound 37), which demonstrated acute mechanism-based pharmacodynamic effects. The combination of in vivo efficacy and attractive rodent pharmacodynamic profiles suggests compounds generated from this series may afford attractive candidates for the treatment of Type 2 diabetes.
Subject(s)
Benzofurans/chemistry , Benzofurans/pharmacology , Propionates/chemistry , Propionates/pharmacology , Receptors, G-Protein-Coupled/agonists , Animals , Benzofurans/blood , Blood Glucose/analysis , Blood Glucose/metabolism , Diabetes Mellitus, Type 2/blood , Diabetes Mellitus, Type 2/drug therapy , Diabetes Mellitus, Type 2/metabolism , Drug Evaluation, Preclinical , High-Throughput Screening Assays , Humans , Hypoglycemic Agents/blood , Hypoglycemic Agents/chemistry , Hypoglycemic Agents/pharmacology , Mice , Propionates/blood , Receptors, G-Protein-Coupled/metabolismABSTRACT
A novel series of benzo-[1,2,4]-triazolo-[1,4]-oxazepine GPR142 agonists are described. The series was designed to address the suboptimal PK (pharmacokinetic) and off-target profile of a class of N-aryl-benzo-[1,4]-oxazepine-4-carboxamides, represented by 1, that were identified from a high-throughput screen of the Merck compound collection for GPR142 agonists. This work led to the discovery of 3-phenoxy-benzo-[1,2,4]-triazolo-[1,4]-oxazepine 47, a potent GPR142 agonist with an off-target and PK profile suitable for in vivo studies. This compound and a related analogue 40 were shown to be active in mouse oral glucose tolerance tests (OGTTs). Furthermore, a GPR142 knock-out mouse OGTT study with compound 40 provides evidence that its glucose-lowering effect is mediated by GPR142.
Subject(s)
Diabetes Mellitus, Experimental/drug therapy , Drug Discovery , Oxazepines/pharmacology , Receptors, G-Protein-Coupled/agonists , Triazoles/pharmacology , Animals , Dose-Response Relationship, Drug , Glucose Tolerance Test , Mice , Mice, Knockout , Molecular Structure , Oxazepines/chemical synthesis , Oxazepines/chemistry , Rats , Receptors, G-Protein-Coupled/deficiency , Structure-Activity Relationship , Triazoles/chemical synthesis , Triazoles/chemistryABSTRACT
Prolylcarboxypeptidase (PrCP) is a serine protease that may have a role in metabolism regulation. A class of reversible, potent, and selective PrCP inhibitors was developed starting from a mechanism based design for inhibiting this serine protease. Compound 8o inhibits human and mouse PrCP at IC(50) values of 1 and 2 nM and is not active (IC(50) > 25 µM) against a panel of closely related proteases. It has lower serum binding than its close analogues and is bioavailable in mouse. Subchronic dosing of 8o in PrCP(-/-) and WT mice at 100 mg/kg for 5 days resulted in a 5% reduction in body weight in WT mice and a 1% reduction in PrCP KO mice.
