RESUMO
Thrombotic diseases are a major cause of death and morbidity. Factor Xa (fXa) plays a vital role in the regulation of normal homeostasis and abnormal intravascular thrombus development in the blood coagulation cascade. A novel series of fXa inhibitors incorporating an amidino 6,5-fused bicyclic moiety at the P1 position has been designed and synthesized based on molecular modeling studies. Structure-activity relationship (SAR) studies have led to selective subnanomolar fXa inhibitors. The most potent fXa inhibitor in this series (72, SE170) has a potent inhibition constant (K(i) = 0.3 nM), is 350-fold selective for fXa over trypsin, and also shows good in vivo efficacy in a rabbit arterio-venous thrombosis model (ID(50) = 0.14 micromol/kg/h). An X-ray crystal structure of 72 complexed to bovine trypsin was completed, and a binding mode of 72 with fXa has been proposed based on modeling with human des-Gla-fXa.
Assuntos
Amidinas/síntese química , Benzimidazóis/síntese química , Inibidores do Fator Xa , Fibrinolíticos/síntese química , Indazóis/síntese química , Indóis/síntese química , Sulfonamidas/síntese química , Amidinas/química , Amidinas/farmacocinética , Amidinas/farmacologia , Animais , Benzimidazóis/química , Benzimidazóis/farmacocinética , Benzimidazóis/farmacologia , Bovinos , Cristalografia por Raios X , Cães , Desenho de Fármacos , Fibrinolíticos/química , Fibrinolíticos/farmacocinética , Fibrinolíticos/farmacologia , Humanos , Indazóis/química , Indazóis/farmacocinética , Indazóis/farmacologia , Indóis/química , Indóis/farmacocinética , Indóis/farmacologia , Modelos Moleculares , Coelhos , Relação Estrutura-Atividade , Sulfonamidas/química , Sulfonamidas/farmacocinética , Sulfonamidas/farmacologia , Tripsina/química , Trombose Venosa/tratamento farmacológicoRESUMO
Thrombin, a serine protease, plays a central role in the initiation of thrombotic events. We report the design, synthesis, and antithrombotic efficacy of XU817 (7), a nonpeptide 5-(amidino) indole thrombin inhibitor. Utilizing the co-crystal structure of XU817 bound in the active site of thrombin we were able to synthesize analogs with enhanced thrombin affinity.
Assuntos
Amidinas/química , Antitrombinas/química , Compostos Heterocíclicos/química , Indóis/química , Amidinas/síntese química , Amidinas/farmacologia , Animais , Antitrombinas/síntese química , Antitrombinas/farmacologia , Desenho de Fármacos , Compostos Heterocíclicos/síntese química , Compostos Heterocíclicos/farmacologia , Ligação de Hidrogênio , Indóis/síntese química , Indóis/farmacologia , Estrutura Molecular , RatosRESUMO
An easily implemented method of measuring in-plane surface displacement by photographing an object through two laterally displaced apertures is described and the experimental results are presented. The displacement is displayed as a pattern of moiré fringes over the image. No previously constructed grids or rulings are required as in normal moiré devices. The method is noncontacting and requires no special surface preparation. The sensitivity is easily adjusted and is shown to be equivalent to that obtained using double-exposure holography or speckle pattern interferometry techniques. The method has potential application in mechanically unstable environments or where the conditions are such that grids or strain gauges cannot be attached to the object.
