RESUMO
From a series of N-acyl 4-(3-pyridonyl)phenylalanine derivatives of 4, the trifluoromethyl derivative 28 was identified as a potent, dual acting alpha4 integrin antagonist with activity in primate models of allergic asthma. Investigation of a series of prodrug esters led to the discovery of the morpholinopropyl derivative 48 that demonstrated good intestinal fluid stability, solubility and permeability. Compound 48 gave high blood levels of 28 when dosed orally in cynomolgus monkeys. Surprisingly, hydrolysis of 48 was rapid in liver microsomes from the pharmacological species, mouse, rat and monkey, but slow in dog and human; in vivo studies also indicated there was prolonged exposure to unchanged prodrug in dogs.
Assuntos
Integrina alfa4beta1/antagonistas & inibidores , Integrinas/antagonistas & inibidores , Fenilalanina/análogos & derivados , Animais , Cães , Ésteres/sangue , Ésteres/farmacologia , Humanos , Camundongos , Fenilalanina/farmacologia , Pró-Fármacos/química , Pró-Fármacos/farmacologia , RatosRESUMO
N-Acyl 4-(5-pyrimidine-2,4-dionyl)phenylalanine derivatives of type 4 were designed to replace the 2,6-dichlorobenzoylamine portion of compound 1 in order to identify novel compounds with improved potency against α4-integrins. Several derivatives were identified as very potent dual-acting α4-integrin, α4ß1 and α4ß7 antagonists. Investigation of a limited number of prodrug esters led to the discovery of the ethyl ester prodrug 42, which demonstrated good intestinal fluid stability and good permeability. Despite low solubility, 42 gave acceptable blood levels of 30 when dosed orally in non-human primates. Additionally, 42 had an overall excellent profile and was selected for clinical trials. Investigation of N-acyl 4-(5-pyrimidine-2,4-dionyl)phenylalanine derivatives led to the discovery of several very potent dual-acting α4-integrin antagonists. Ethyl ester prodrug 42 advanced to human clinical trials based on the excellent intestinal fluid stability, good permeability and superior efficacy in non-human primates.
Assuntos
Integrina alfa4beta1/antagonistas & inibidores , Integrinas/antagonistas & inibidores , Fenilalanina/análogos & derivados , Pirimidinas/farmacologia , Animais , Cães , Ésteres/química , Ésteres/farmacocinética , Ésteres/farmacologia , Humanos , Macaca fascicularis , Camundongos , Fenilalanina/farmacocinética , Fenilalanina/farmacologia , Pró-Fármacos/química , Pró-Fármacos/farmacocinética , Pró-Fármacos/farmacologia , Pirimidinas/química , Pirimidinas/farmacocinética , Ratos , Relação Estrutura-AtividadeRESUMO
RO4396686 is a small molecule KDR, FGFR, and PDGFR inhibitor with good pharmacokinetic properties in rodents. In a mouse corneal neovascularization assay, this compound inhibited VEGF-induced angiogenesis. Tested in a H460a xenograft tumor model this agent effected significant tumor growth inhibition at doses as low as 50mg/kg.
Assuntos
Inibidores da Angiogênese/farmacologia , Neoplasias Experimentais/irrigação sanguínea , Neovascularização Patológica , Pirimidinas/farmacologia , Inibidores da Angiogênese/química , Animais , Camundongos , Camundongos Nus , Ratos , Ratos Wistar , Receptores de Fatores de Crescimento de Fibroblastos/antagonistas & inibidores , Receptores do Fator de Crescimento Derivado de Plaquetas/antagonistas & inibidores , Fator A de Crescimento do Endotélio Vascular/fisiologia , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidoresRESUMO
(+/-)-1-(anti-3-Hydroxy-cyclopentyl)-3-(4-methoxy-phenyl)-7-phenylamino-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one (RO4383596) is a potent and selective inhibitor of the pro-angiogenic receptor tyrosine kinases KDR, FGFR, and PDGFR. This agent has an excellent pharmacokinetic profile and is highly efficacious in rodent models of angiogenesis upon oral administration.