Design, synthesis, and activity of 2,6-diphenoxypyridine-derived factor Xa inhibitors

G Phillips; D D Davey; K A Eagen; S K Koovakkat; A Liang; H P Ng; M Pinkerton; L Trinh; M Whitlow; A M Beatty; M M Morrissey

doi:10.1021/jm980667k

Design, synthesis, and activity of 2,6-diphenoxypyridine-derived factor Xa inhibitors

J Med Chem. 1999 May 20;42(10):1749-56. doi: 10.1021/jm980667k.

Authors

G Phillips¹, D D Davey, K A Eagen, S K Koovakkat, A Liang, H P Ng, M Pinkerton, L Trinh, M Whitlow, A M Beatty, M M Morrissey

Affiliation

¹ Discovery Research, Berlex Biosciences, 15049 San Pablo Avenue, P.O. Box 4099, Richmond, California 94804-0099, USA.

PMID: 10346927
DOI: 10.1021/jm980667k

Abstract

A novel series of 2,6-diphenoxypyridines has been designed to inhibit factor Xa, a serine protease strategically located in the coagulation cascade. The evolution from the photochemically unstable bisamidine (Z,Z)-BABCH to potent bisamidine compounds with a pyridine heterocycle as the core scaffold has been achieved. The most potent compound in the series, 6h, has a Ki for human factor Xa of 12 nM. The selectivity of 6h against bovine trypsin and human thrombin was greater than 90- and 1000-fold, respectively. Two proposed modes of binding of 6h to factor Xa are made based on the crystal structures of 6h by itself and of 6h bound to bovine trypsin.

MeSH terms

Amidines / chemical synthesis*
Amidines / chemistry
Animals
Cattle
Crystallography, X-Ray
Drug Design
Factor Xa Inhibitors*
Fibrinolytic Agents / chemical synthesis*
Fibrinolytic Agents / chemistry
Humans
Models, Molecular
Molecular Conformation
Pyridines / chemical synthesis*
Pyridines / chemistry
Stereoisomerism
Structure-Activity Relationship
Thrombin / antagonists & inhibitors
Trypsin Inhibitors / chemical synthesis
Trypsin Inhibitors / chemistry

Substances

3,3'-(3,5-difluoro-4-methyl-2,6-pyridinediylbis(oxy))bis(benzenecarbox(imide)amide)
Amidines
Factor Xa Inhibitors
Fibrinolytic Agents
Pyridines
Trypsin Inhibitors
Thrombin