RESUMO
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.
Assuntos
Cicloexanóis/química , Isoxazóis/química , Canais de Cátion TRPV/antagonistas & inibidores , Administração Oral , Amidas/química , Amidas/farmacocinética , Amidas/uso terapêutico , Animais , Capsaicina/toxicidade , Cicloexanóis/farmacocinética , Cicloexanóis/uso terapêutico , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Humanos , Hiperalgesia/induzido quimicamente , Hiperalgesia/tratamento farmacológico , Isoxazóis/farmacocinética , Isoxazóis/uso terapêutico , Microssomos Hepáticos/metabolismo , Ratos , Relação Estrutura-Atividade , Canais de Cátion TRPV/metabolismoRESUMO
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.
Assuntos
Amidas/química , Anti-Hipertensivos/química , Cicloexanóis/química , Isoxazóis/química , Canais de Cátion TRPV/antagonistas & inibidores , Amidas/síntese química , Amidas/farmacocinética , Animais , Anti-Hipertensivos/síntese química , Anti-Hipertensivos/farmacocinética , Cicloexanóis/síntese química , Cicloexanóis/farmacocinética , Hipertermia Induzida , Isoxazóis/síntese química , Isoxazóis/farmacocinética , Ratos , Ratos Wistar , Relação Estrutura-Atividade , Canais de Cátion TRPV/metabolismoRESUMO
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.
Assuntos
Anti-Hipertensivos/química , Hipertensão/tratamento farmacológico , Inibidores de Proteínas Quinases/química , Pirimidinas/química , Triazinas/química , Quinases Associadas a rho/antagonistas & inibidores , Animais , Anti-Hipertensivos/síntese química , Anti-Hipertensivos/farmacologia , Sítios de Ligação , Simulação por Computador , Modelos Animais de Doenças , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/síntese química , Pirimidinas/farmacologia , Ratos , Relação Estrutura-Atividade , Triazinas/síntese química , Triazinas/farmacologia , Quinases Associadas a rho/metabolismoRESUMO
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.
Assuntos
Integrina alfaVbeta3/antagonistas & inibidores , Receptores de Vitronectina/antagonistas & inibidores , Disponibilidade Biológica , Linhagem Celular , Humanos , Compostos Macrocíclicos/farmacocinética , Compostos Macrocíclicos/farmacologia , Relação Estrutura-AtividadeRESUMO
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.