Design, synthesis, and biological evaluation of potent and selective amidino bicyclic factor Xa inhibitors.
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.
Han
Q
Q
DuPont Pharmaceuticals Company, Experimental Station, P.O. Box 80500, Wilmington, Delaware 19880-0500, USA. qi.han@dupontpharma.com
Dominguez
C
C
Stouten
P F
PF
Park
J M
JM
Duffy
D E
DE
Galemmo
R A
RA
Rossi
K A
KA
Alexander
R S
RS
Smallwood
A M
AM
Wong
P C
PC
Wright
M M
MM
Luettgen
J M
JM
Knabb
R M
RM
Wexler
R R
RR
D000578:Amidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D001562:Benzimidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D002417:Cattle; D018360:Crystallography, X-Ray; D004285:Dogs; D015195:Drug Design; D065427:Factor Xa Inhibitors; D005343:Fibrinolytic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D006801:Humans; D007191:Indazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D008958:Models, Molecular; D011817:Rabbits; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D014357:Trypsin / Q000737:chemistry; D020246:Venous Thrombosis / Q000188:drug therapy
D000578:Amidines; D001562:Benzimidazoles; D065427:Factor Xa Inhibitors; D005343:Fibrinolytic Agents; D007191:Indazoles; D007211:Indoles; C416651:SE 170; D013449:Sulfonamides; D014357:Trypsin