RESUMO
The synthesis and structure-activity relationship (SAR) analysis of a novel series of trialkoxyaryl derivatives, as specific and competitive inhibitors of platelet activating factor (PAF), are described. Molecular modeling comparisons of PAF with the known antagonists Ginkgolide B and L-652731 led to the selection of N-[2-[(3,4,5-trimethoxybenzoyl)oxy]ethyl]-N,N,N-trimethylammonium iodide (1) from the Wellcome registry of compounds and to the synthesis of the lead compound N-[2-[[4-(hexyloxy)-3,5-dimethoxybenzoyl]oxy]ethyl]-N,N,N- trimethylammonium iodide (3, pKb 5.43). Further SAR considerations directed the design to 2-(hexyloxy)-1,3-dimethoxy-5-[4-(4-methylthiazol-5-yl)butyl] benzene (38) (pKb 7.14), a novel, specific, and competitive inhibitor of the PAF receptor in rabbit-washed platelets.
Assuntos
Fator de Ativação de Plaquetas/antagonistas & inibidores , Compostos de Amônio Quaternário/síntese química , Animais , Sítios de Ligação , Plaquetas/efeitos dos fármacos , Plaquetas/metabolismo , Células Cultivadas , Masculino , Inibidores da Agregação Plaquetária/farmacologia , Compostos de Amônio Quaternário/metabolismo , Compostos de Amônio Quaternário/farmacologia , Coelhos , Relação Estrutura-AtividadeRESUMO
BW245C analogues which have 15'-keto, -oximino, -sulphinyl, -sulphonyl, -methyl, -1-adamantyl, 14'-hydroxy, 16'-hydroxy, 13'-14'-NH=CH, -NH-CH2, or -NH-CO groups have been synthesized and evaluated for their activity in inhibiting platelet aggregation and for their cardiovascular actions: the 13'-aza analogues 13 and 14 are more potent inhibitors of human platelet aggregation than BW245C (0.3, 0.6 and 0.2 x PGI2, respectively) and these inhibitory activities on platelet aggregation increase on incubation in vitro. The prostaglandin mimetic properties of 13 (BW68C) and 14 (BW361C) were studied in more detail and their platelet inhibitory and vasodilatory effects found to be of longer duration than those of BW245C. All other modifications to the omega-chain of BW245C led to less potent or inactive compounds.
Assuntos
Hidantoínas/síntese química , Hidantoínas/farmacologia , Inibidores da Agregação Plaquetária/síntese química , Agregação Plaquetária/efeitos dos fármacos , Animais , Cães , Hemodinâmica/efeitos dos fármacos , Humanos , Técnicas In Vitro , Masculino , Inibidores da Agregação Plaquetária/farmacologia , Coelhos , Ratos , Ratos Wistar , Relação Estrutura-Atividade , Vasodilatadores/síntese química , Vasodilatadores/farmacologiaRESUMO
Isomazole analogues which have achiral electron withdrawing substituents at the 4'-position and analogues with heterocyclic 'C' rings have been synthesized and evaluated as inotropic agents. It was found that pyridyl could replace phenyl in the 'C' ring without loss of activity. The 4'-methylsulphonyl, -cyano, -carboxamido, and acetyl analogues had similar inotropic potencies to Isomazole whilst displaying superior cardiovascular profiles in in vivo studies.