RESUMEN
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.
Asunto(s)
Benzofuranos/química , Benzofuranos/farmacología , Propionatos/química , Propionatos/farmacología , Receptores Acoplados a Proteínas G/agonistas , Animales , Benzofuranos/sangre , Glucemia/análisis , Glucemia/metabolismo , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Evaluación Preclínica de Medicamentos , Ensayos Analíticos de Alto Rendimiento , Humanos , Hipoglucemiantes/sangre , Hipoglucemiantes/química , Hipoglucemiantes/farmacología , Ratones , Propionatos/sangre , Receptores Acoplados a Proteínas G/metabolismoRESUMEN
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.
Asunto(s)
Diabetes Mellitus Experimental/tratamiento farmacológico , Descubrimiento de Drogas , Oxazepinas/farmacología , Receptores Acoplados a Proteínas G/agonistas , Triazoles/farmacología , Animales , Relación Dosis-Respuesta a Droga , Prueba de Tolerancia a la Glucosa , Ratones , Ratones Noqueados , Estructura Molecular , Oxazepinas/síntesis química , Oxazepinas/química , Ratas , Receptores Acoplados a Proteínas G/deficiencia , Relación Estructura-Actividad , Triazoles/síntesis química , Triazoles/químicaRESUMEN
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.