RESUMO
A number of new amine scaffolds with good inhibitory activity in the ADP-induced platelet aggregation assay have been found to be potent antagonists of the P2Y1 receptor. SAR optimization led to the identification of isoindoline 3c and piperidine 4a which showed good in vitro binding and functional activities, as well as improved aqueous solubility. Among them, the piperidine 4a showed the best overall profile with favorable PK parameters.
Assuntos
Aminas/química , Agonistas do Receptor Purinérgico P2Y/química , Receptores Purinérgicos P2Y1/química , Ureia/análogos & derivados , Difosfato de Adenosina/farmacologia , Aminas/síntese química , Aminas/farmacocinética , Animais , Plaquetas/efeitos dos fármacos , Plaquetas/metabolismo , Meia-Vida , Humanos , Microssomos Hepáticos/metabolismo , Piperidinas/química , Inibidores da Agregação Plaquetária/síntese química , Inibidores da Agregação Plaquetária/química , Inibidores da Agregação Plaquetária/farmacocinética , Ligação Proteica , Agonistas do Receptor Purinérgico P2Y/síntese química , Agonistas do Receptor Purinérgico P2Y/farmacocinética , Ratos , Receptores Purinérgicos P2Y1/metabolismo , Relação Estrutura-Atividade , Ureia/síntese química , Ureia/farmacocinéticaRESUMO
Preclinical antithrombotic efficacy and bleeding models have demonstrated that P2Y1 antagonists are efficacious as antiplatelet agents and may offer a safety advantage over P2Y12 antagonists in terms of reduced bleeding liabilities. In this article, we describe the structural modification of the tert-butyl phenoxy portion of lead compound 1 and the subsequent discovery of a novel series of conformationally constrained ortho-anilino diaryl ureas. In particular, spiropiperidine indoline-substituted diaryl ureas are described as potent, orally bioavailable small-molecule P2Y1 antagonists with improved activity in functional assays and improved oral bioavailability in rats. Homology modeling and rat PK/PD studies on benchmark compound 3l will also be presented. Compound 3l was our first P2Y1 antagonist to demonstrate a robust oral antithrombotic effect with mild bleeding liability in the rat thrombosis and hemostasis models.
Assuntos
Desenho de Fármacos , Conformação Molecular , Compostos de Fenilureia/farmacologia , Compostos de Fenilureia/farmacocinética , Antagonistas do Receptor Purinérgico P2Y/farmacologia , Antagonistas do Receptor Purinérgico P2Y/farmacocinética , Receptores Purinérgicos P2Y1/metabolismo , Compostos de Espiro/farmacologia , Compostos de Espiro/farmacocinética , Ureia/farmacologia , Ureia/farmacocinética , Animais , Disponibilidade Biológica , Humanos , Indóis/química , Modelos Moleculares , Compostos de Fenilureia/química , Compostos de Fenilureia/metabolismo , Antagonistas do Receptor Purinérgico P2Y/química , Antagonistas do Receptor Purinérgico P2Y/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores Purinérgicos P2Y1/química , Homologia de Sequência de Aminoácidos , Compostos de Espiro/química , Compostos de Espiro/metabolismo , Ureia/química , Ureia/metabolismoRESUMO
Five-membered-ring heterocyclic urea mimics have been found to be potent and selective antagonists of the P2Y1 receptor. SAR of the various heterocyclic replacements is presented, as well as side-chain SAR of the more potent thiadiazole ring system which leads to thiadiazole 4c as a new antiplatelet agent.
Assuntos
Antagonistas do Receptor Purinérgico P2Y/química , Antagonistas do Receptor Purinérgico P2Y/farmacologia , Receptores Purinérgicos P2Y1/química , Tiadiazóis/química , Tiadiazóis/farmacologia , Materiais Biomiméticos/química , Materiais Biomiméticos/farmacologia , Humanos , Cinética , Ligação Proteica , Relação Estrutura-Atividade , Ureia/químicaRESUMO
We report herein a series of substituted N-(1H-pyrrolo[2,3-b]pyridin-5-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amines as inhibitors of vascular endothelial growth factor receptor-2 tyrosine kinase. Through structure-activity relationship studies, biochemical potency, pharmacokinetics, and kinase selectivity were optimized to afford BMS-645737 (13), a compound with good preclinical in vivo activity against human tumor xenograft models.