Design, synthesis, and biological evaluation of potent and selective amidino bicyclic factor Xa inhibitors

Q Han; C Dominguez; P F Stouten; J M Park; D E Duffy; R A Galemmo Jr; K A Rossi; R S Alexander; A M Smallwood; P C Wong; M M Wright; J M Luettgen; R M Knabb; R R Wexler

doi:10.1021/jm000113t

Design, synthesis, and biological evaluation of potent and selective amidino bicyclic factor Xa inhibitors

J Med Chem. 2000 Nov 16;43(23):4398-415. doi: 10.1021/jm000113t.

Authors

Q Han¹, C Dominguez, P F Stouten, J M Park, D E Duffy, R A Galemmo Jr, K A Rossi, R S Alexander, A M Smallwood, P C Wong, M M Wright, J M Luettgen, R M Knabb, R R Wexler

Affiliation

¹ DuPont Pharmaceuticals Company, Experimental Station, P.O. Box 80500, Wilmington, Delaware 19880-0500, USA. qi.han@dupontpharma.com

PMID: 11087565
DOI: 10.1021/jm000113t

Abstract

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.

MeSH terms

Amidines / chemical synthesis*
Amidines / chemistry
Amidines / pharmacokinetics
Amidines / pharmacology
Animals
Benzimidazoles / chemical synthesis*
Benzimidazoles / chemistry
Benzimidazoles / pharmacokinetics
Benzimidazoles / pharmacology
Cattle
Crystallography, X-Ray
Dogs
Drug Design
Factor Xa Inhibitors*
Fibrinolytic Agents / chemical synthesis*
Fibrinolytic Agents / chemistry
Fibrinolytic Agents / pharmacokinetics
Fibrinolytic Agents / pharmacology
Humans
Indazoles / chemical synthesis*
Indazoles / chemistry
Indazoles / pharmacokinetics
Indazoles / pharmacology
Indoles / chemical synthesis*
Indoles / chemistry
Indoles / pharmacokinetics
Indoles / pharmacology
Models, Molecular
Rabbits
Structure-Activity Relationship
Sulfonamides / chemical synthesis*
Sulfonamides / chemistry
Sulfonamides / pharmacokinetics
Sulfonamides / pharmacology
Trypsin / chemistry
Venous Thrombosis / drug therapy

Substances

Amidines
Benzimidazoles
Factor Xa Inhibitors
Fibrinolytic Agents
Indazoles
Indoles
SE 170
Sulfonamides
Trypsin