RESUMEN
Optimization of a 5-oxopyrrolopyridine series based upon structure-activity relationships (SARs) developed from our previous efforts on a number of related bicyclic series yielded compound 2s (BMS-767778) with an overall activity, selectivity, efficacy, PK, and developability profile suitable for progression into the clinic. SAR in the series and characterization of 2s are described.
Asunto(s)
Acetamidas/química , Acetamidas/farmacología , Compuestos Bicíclicos Heterocíclicos con Puentes/química , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Dipeptidil Peptidasa 4/metabolismo , Inhibidores de la Dipeptidil-Peptidasa IV/química , Inhibidores de la Dipeptidil-Peptidasa IV/farmacología , Diseño de Fármacos , Pirroles/química , Pirroles/farmacología , Acetamidas/síntesis química , Animales , Compuestos Bicíclicos Heterocíclicos con Puentes/síntesis química , Dominio Catalítico , Dipeptidil Peptidasa 4/química , Inhibidores de la Dipeptidil-Peptidasa IV/síntesis química , Prueba de Tolerancia a la Glucosa , Humanos , Masculino , Ratones , Modelos Moleculares , Pirroles/síntesis química , Especificidad por SustratoRESUMEN
Design, synthesis, and SAR of 7-oxopyrrolopyridine-derived DPP4 inhibitors are described. The preferred stereochemistry of these atropisomeric biaryl analogs has been identified as Sa. Compound (+)-3t, with a K(i) against DPP4, DPP8, and DPP9 of 0.37 nM, 2.2, and 5.7 µM, respectively, showed a significant improvement in insulin response after single doses of 3 and 10 µmol/kg in ob/ob mice.