RESUMO
The 4-amino-5-azaindole as an amidino-benzimidazole replacement is described. A series of potent and selective analogs were discovered and showed desirable ex vivo efficacy as measured by PT.
Assuntos
Fator VIIa/antagonistas & inibidores , Indóis/síntese química , Indóis/farmacologia , Piridinas/síntese química , Piridinas/farmacologia , Fator VIIa/metabolismo , Indóis/química , Estrutura Molecular , Piridinas/química , Relação Estrutura-AtividadeRESUMO
The discovery and development of 5-azaindole factor VIIa inhibitors will be described.
Assuntos
Compostos Aza/síntese química , Compostos Aza/farmacologia , Fator VIIa/antagonistas & inibidores , Indóis/síntese química , Indóis/farmacologia , Compostos Aza/química , Cristalografia por Raios X , Fator VIIa/química , Fator VIIa/metabolismo , Indóis/química , Modelos Moleculares , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
Within the trypsin family of coagulation proteases, obtaining highly selective inhibitors of factor VIIa has been challenging. We report a series of factor VIIa (fVIIa) inhibitors based on the 5-amidino-2-(2-hydroxy-biphenyl-3-yl)-benzimidazole (1) scaffold with potency for fVIIa and high selectivity against factors IIa, Xa, and trypsin. With this scaffold class, we propose that a unique hydrogen bond interaction between a hydroxyl on the distal ring of the biaryl system and the backbone carbonyl of fVIIa lysine-192 provides a basis for enhanced selectivity and potency for fVIIa.
Assuntos
Fator VIIa/antagonistas & inibidores , Sítios de Ligação , Inibidores do Fator Xa , Humanos , Ligação de Hidrogênio , Ligação Proteica , Protrombina/antagonistas & inibidores , Relação Estrutura-Atividade , Tripsina/metabolismoRESUMO
The rational design and synthesis of beta-amino-alpha-hydroxy amide derivatives as reversible inhibitors of methionine aminopeptidase-2 (MetAP2) with anti-proliferative activity against human umbilical vein endothelial cells (HUVECs) is described.
Assuntos
Amidas/síntese química , Aminopeptidases/antagonistas & inibidores , Desenho de Fármacos , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/enzimologia , Glicoproteínas/antagonistas & inibidores , Inibidores de Proteases/síntese química , Amidas/farmacologia , Aminopeptidases/metabolismo , Animais , Bovinos , Glicoproteínas/metabolismo , Humanos , Metionil Aminopeptidases , Inibidores de Proteases/farmacologiaRESUMO
Two new alkaloids, polycarpine (1) and N,N-didesmethylgrossularine-1 (4), have been isolated from extracts of the ascidian Polycarpa aurata collected in Chuuk, Federated States of Micronesia. Three degradation products of 1 were also isolated. The structures of 1, 2, and 4 were determined by X-ray crystallography. The dimeric disulfide 1 inhibited the enzyme inosine monophosphate dehydrogenase, but the inhibition could be reversed by addition of excess dithiothreitol suggesting that 1 reacts with sulfhydryl groups on the enzyme.