RESUMEN
Systematic optimisation of a poorly soluble lead series of isoxazole-3-carboxamides was conducted. Substitution of the 4-position with specific polar functionality afforded the requisite balance of potency, solubility and physicochemical properties. Compound 21a was found to be efficacious in the rat Capsaicin Hargreaves assay following oral administration.
Asunto(s)
Ciclohexanoles/química , Isoxazoles/química , Canales Catiónicos TRPV/antagonistas & inhibidores , Administración Oral , Amidas/química , Amidas/farmacocinética , Amidas/uso terapéutico , Animales , Capsaicina/toxicidad , Ciclohexanoles/farmacocinética , Ciclohexanoles/uso terapéutico , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos , Humanos , Hiperalgesia/inducido químicamente , Hiperalgesia/tratamiento farmacológico , Isoxazoles/farmacocinética , Isoxazoles/uso terapéutico , Microsomas Hepáticos/metabolismo , Ratas , Relación Estructura-Actividad , Canales Catiónicos TRPV/metabolismoRESUMEN
Optimisation of a screening hit incorporating both TRPV1 activity and solubility was conducted. Substitution of the isoxazole-3-carboxamide with the bespoke 1S, 3R-3-aminocyclohexanol motif afforded the requisite balance of potency and solubility. Compounds 32 and 40 were found to have antihyperalgesic effects in the rat CFA Hg assay and induce a mechanism based hyperthermia.
Asunto(s)
Amidas/química , Antihipertensivos/química , Ciclohexanoles/química , Isoxazoles/química , Canales Catiónicos TRPV/antagonistas & inhibidores , Amidas/síntesis química , Amidas/farmacocinética , Animales , Antihipertensivos/síntesis química , Antihipertensivos/farmacocinética , Ciclohexanoles/síntesis química , Ciclohexanoles/farmacocinética , Hipertermia Inducida , Isoxazoles/síntesis química , Isoxazoles/farmacocinética , Ratas , Ratas Wistar , Relación Estructura-Actividad , Canales Catiónicos TRPV/metabolismoRESUMEN
The profile of a series of triazine and pyrimidine based ROCK inhibitors is described. An initial binding mode was established based on a homology model and the proposed interactions are consistent with the observed SAR. Compounds from the series are potent in a cell migration assay and possess a favorable kinase selectivity. In vivo activity was demonstrated for compound 1A in a spontaneous hypertensive rat model.
Asunto(s)
Antihipertensivos/química , Hipertensión/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/química , Pirimidinas/química , Triazinas/química , Quinasas Asociadas a rho/antagonistas & inhibidores , Animales , Antihipertensivos/síntesis química , Antihipertensivos/farmacología , Sitios de Unión , Simulación por Computador , Modelos Animales de Enfermedad , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/farmacología , Pirimidinas/síntesis química , Pirimidinas/farmacología , Ratas , Relación Estructura-Actividad , Triazinas/síntesis química , Triazinas/farmacología , Quinasas Asociadas a rho/metabolismoRESUMEN
The discovery, synthesis and preliminary SAR of a novel class of non-peptidic antagonists of the alpha(v)-integrins alpha(v)beta(3) and alpha(v)beta(5) is described. High-throughput screening of an extensive series of ECLiPStrade mark compound libraries led to the identification of compound 1 as a dual inhibitor of the alpha(v)-integrins alpha(v)beta(3) and alpha(v)beta(5). Optimization of compound 1 involving, in part, introduction of two novel constraints led to the discovery of compounds 15a and 15b with reduced PSA and much improved potency for both the alpha(v)beta(3) and alpha(v)beta(5) integrins. Compounds 15a and 15b were shown to have promising activity in functional cellular assays and compound 15a also exhibited a promising Caco-2 permeability profile.
Asunto(s)
Integrina alfaVbeta3/antagonistas & inhibidores , Receptores de Vitronectina/antagonistas & inhibidores , Disponibilidad Biológica , Línea Celular , Humanos , Compuestos Macrocíclicos/farmacocinética , Compuestos Macrocíclicos/farmacología , Relación Estructura-ActividadRESUMEN
An imidazolylpyrimidine was identified in a CXCR2 chemokine receptor antagonist screen and was optimized for potency, in vitro metabolic stability, and oral bioavailability. It was found that subtle structural modification within the series affected the oral bioavailability. Potent and orally available CXCR2 antagonists are herein reported.