RESUMO
The synthesis and in vitro evaluation of the acetamidine derivatives of hetero-substituted lysine and homolysine analogues have identified potent inhibitors of human nitric oxide synthase enzymes, including examples with marked selectivity for the inducible isoform.
Assuntos
Acetamidas/síntese química , Inibidores Enzimáticos/síntese química , Lisina/análogos & derivados , Lisina/síntese química , Óxido Nítrico Sintase/antagonistas & inibidores , Acetamidas/farmacologia , Inibidores Enzimáticos/farmacologia , Humanos , Indicadores e Reagentes , Isoenzimas/antagonistas & inibidores , Lisina/farmacologia , Óxido Nítrico Sintase Tipo II , Ornitina/análogos & derivados , Ornitina/farmacologia , Sulfetos/farmacologia , Sulfonas/farmacologiaRESUMO
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-AtividadeAssuntos
Inibidores Enzimáticos , Cinurenina/biossíntese , Compostos Orgânicos , Triptofano Oxigenase/antagonistas & inibidores , Triptofano/metabolismo , Animais , Ansiedade/fisiopatologia , Encéfalo/metabolismo , Ácido Hidroxi-Indolacético/metabolismo , Fígado/metabolismo , Ratos , Serotonina/biossíntese , Triptofano/farmacocinética , Triptofano Oxigenase/farmacologiaRESUMO
The interaction of novel diacylglycerol analogues at the recognition site on protein kinase C has been evaluated using a modified [3H]phorbol dibutyrate binding assay and an established kinase activation assay. Studies with the 3-methyl analogues of 1,2-dihexanoyl-sn-glycerol have revealed a preferred stereochemical configuration at the C-3 position. Other chemical modifications have extended existing structure/activity relationships by showing that carbamates and sulphonyl esters cannot substitute for carboxylate esters and that cyclic acyl groups are active. Thus, most, if not all of the functionalities in the diacylglycerol molecule are required for interaction at the receptor on protein kinase C. Stereochemical specificity is required at C2 and C3.