RESUMEN
Herein we describe the development of a series of pyrazolopyrimidinone phosphodiesterase 2A (PDE2) inhibitors using structure-guided lead identification and design. The series was derived from informed chemotype replacement based on previously identified internal leads. The initially designed compound 3, while potent on PDE2, displayed unsatisfactory selectivity against the other PDE2 isoforms. Compound 3 was subsequently optimized for improved PDE2 activity and isoform selectivity. Insights into the origins of PDE2 selectivity are described and verified using cocrystallography. An optimized lead, 4, demonstrated improved performance in both a rodent and a nonhuman primate cognition model.
RESUMEN
A new class of CGRP receptor antagonists was identified by replacing the central amide of a previously identified anilide lead structure with ethylene, ethane, or ethyne linkers. (E)-Alkenes as well as alkynes were found to preserve the proper bioactive conformation of the amides, necessary for efficient receptor binding. Further exploration resulted in several potent compounds against CGRP-R with low susceptibility to P-gp mediated efflux.
Asunto(s)
Alquenos/farmacología , Antagonistas del Receptor Peptídico Relacionado con el Gen de la Calcitonina , Alquenos/síntesis química , Alquenos/química , Amidas/química , Relación Dosis-Respuesta a Droga , Células HEK293 , Humanos , Estructura Molecular , Relación Estructura-ActividadRESUMEN
During our ongoing efforts to develop a small molecule inhibitor targeting the beta-amyloid cleaving enzyme (BACE-1), we discovered a class of compounds bearing an aminoimidazole motif. Initial optimization led to potent compounds that have high Pgp efflux ratios. Crystal structure-aided design furnished conformationally constrained compounds that are both potent and have relatively low Pgp efflux ratios. Computational studies performed after these optimizations suggest that the introduction of the constraint enhances potency via additional hydrophobic interactions rather than conformational restriction.
Asunto(s)
Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Imidazoles/química , Inhibidores de Proteasas/química , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Sitios de Unión , Dominio Catalítico , Cristalografía por Rayos X , Diseño de Fármacos , Humanos , Imidazoles/síntesis química , Imidazoles/farmacología , Conformación Molecular , Inhibidores de Proteasas/síntesis química , Inhibidores de Proteasas/farmacología , Estructura Terciaria de ProteínaRESUMEN
A small molecule inhibitor of beta-secretase with a unique binding mode has been developed. Crystallographic determination of the enzyme-inhibitor complex shows the catalytic aspartate residues in the active site are not engaged in inhibitor binding. This unprecedented binding mode in the field of aspartyl protease inhibition is described.
