RESUMEN
We report the discovery of a novel series of spiroindoline-based inhibitors of Sky kinase that bind in the ATP-binding site and exhibit high levels of kinome selectivity through filling the Ala571-subpocket. These inhibitors exhibit moderate oral bioavailability in the rat due to low absorption across the gut wall.
Asunto(s)
Química Farmacéutica/métodos , Intestinos/efectos de los fármacos , Proteínas Tirosina Quinasas Receptoras/antagonistas & inhibidores , Absorción , Adenosina Trifosfato/química , Administración Oral , Animales , Sitios de Unión , Disponibilidad Biológica , Cristalografía por Rayos X/métodos , Diseño de Fármacos , Humanos , Concentración 50 Inhibidora , Modelos Químicos , Agregación Plaquetaria , Ratas , Proteínas Tirosina Quinasas Receptoras/químicaRESUMEN
Novel 2,4-diaminopyrimidine-based small molecule renin inhibitors are disclosed. Through high throughput screening, parallel synthesis, X-ray crystallography, and structure based drug design, we have developed the first non-chiral, non-peptidic, small molecular template to possess moderate potency against renin. The designed compounds consist of a novel 6-ethyl-5-(1,2,3,4-tetrahydroquinolin-7-yl)pyrimidine-2,4-diamine ring system that exhibit moderate potency (IC(50): 91-650 nM) against renin while remaining 'Rule-of-five' compliant.
Asunto(s)
Química Farmacéutica/métodos , Pirimidinas/química , Renina/antagonistas & inhibidores , Animales , Cristalografía por Rayos X , Diseño de Fármacos , Concentración 50 Inhibidora , Modelos Químicos , Modelos Moleculares , Conformación Molecular , Pirimidinas/síntesis química , Pirimidinas/farmacología , Ratas , Ratas Sprague-Dawley , Relación Estructura-ActividadRESUMEN
We report the design and synthesis of a series of 6-(2,4-diaminopyrimidinyl)-1,4-benzoxazin-3-ones as orally bioavailable small molecule inhibitors of renin. Compounds with a 2-methyl-2-aryl substitution pattern exhibit potent renin inhibition and good permeability, solubility, and metabolic stability. Oral bioavailability was found to be dependent on metabolic clearance and cellular permeability, and was optimized through modulation of the sidechain that binds in the S3(sp) subsite.
Asunto(s)
Benzoxazinas/química , Benzoxazinas/farmacología , Diseño de Fármacos , Piridinas/química , Renina/antagonistas & inhibidores , Aminación , Animales , Benzoxazinas/síntesis química , Benzoxazinas/metabolismo , Cristalografía por Rayos X , Masculino , Modelos Moleculares , Estructura Molecular , Ratas , Ratas Sprague-Dawley , Renina/química , Renina/metabolismo , Relación Estructura-ActividadRESUMEN
A systematic investigation of the S3 sub-pocket activity requirements was conducted. It was observed that linear and sterically small side chain substituents are preferred in the S3 sub-pocket for optimal renin inhibition. Polar groups in the S3-sub-pocket were not well tolerated and caused a reduction in renin inhibitory activity. Further, compounds with clog P's < or = 3 demonstrated a dramatic reduction in CYP3A4 inhibitory activity.