RESUMEN
The influence of aromatic substitution on a newly discovered class of inhibitors of dipeptidyl peptidase IV was investigated. A 10(5)-fold increase in potency was achieved by the optimization of aromatic substituents in a parallel chemistry program. The observed SAR could be explained by an X-ray structure of the protein-ligand complex.
Asunto(s)
Inhibidores de la Adenosina Desaminasa , Glicoproteínas/antagonistas & inhibidores , Inhibidores de Proteasas/química , Pirimidinas/química , Adenosina Desaminasa/metabolismo , Glicoproteínas/metabolismo , Inhibidores de Proteasas/metabolismo , Pirimidinas/metabolismoRESUMEN
In a novel series of DPP-IV inhibitors, a large increase of inhibitory activity was achieved by optimisation of aromatic substituents and conformational restriction.
Asunto(s)
Aminas/química , Dipeptidil Peptidasa 4/efectos de los fármacos , Inhibidores Enzimáticos/síntesis química , Piridinas/síntesis química , Células Cultivadas , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Dipeptidil Peptidasa 4/metabolismo , Inhibidores Enzimáticos/metabolismo , Inhibidores Enzimáticos/farmacología , Hidrocarburos Aromáticos/química , Hidrocarburos Aromáticos/farmacología , Concentración 50 Inhibidora , Piridinas/metabolismo , Piridinas/farmacología , Relación Estructura-ActividadRESUMEN
A recently identified DPP-IV inhibitor (1) was found to induce phospholipidosis and to inhibit CYP3A4. A small series of less lipophilic and less amphiphilic analogues was synthesized in an effort to overcome these issues. One compound from this series was equipotent to 1, did not induce phospholipidosis and showed a reduced CYP3A4 inhibition.