Discovery of an orally efficacious inhibitor of coagulation factor Xa which incorporates a neutral P1 ligand.
The discovery and SAR of ketopiperazino methylazaindole factor Xa inhibitors are described. Structure-activity data suggesting that this class of inhibitors does not bind in the canonical mode were confirmed by an X-ray crystal structure showing the neutral haloaromatic bound in the S(1) subsite. The most potent azaindole, 33 (RPR209685), is selective against related serine proteases and attains higher levels of exposure upon oral dosing than comparable benzamidines and benzamidine isosteres. Compound 33 was efficacious in the canine AV model of thrombosis.
Choi-Sledeski
Yong Mi
YM
Department of Medicinal Chemistry and Department of Biology, Aventis Pharmaceuticals, Route 202-206, Bridgewater, New Jersey 08807-0800, USA. yong-mi.choi@aventis.com
Kearney
Robert
R
Poli
Gregory
G
Pauls
Henry
H
Gardner
Charles
C
Gong
Yong
Y
Becker
Michael
M
Davis
Roderick
R
Spada
Alfred
A
Liang
Guyan
G
Chu
Valeria
V
Brown
Karen
K
Collussi
Dennis
D
Leadley
Robert
R
Rebello
Sam
S
Moxey
Phillip
P
Morgan
Suzanne
S
Bentley
Ross
R
Kasiewski
Charles
C
Maignan
Sebastien
S
Guilloteau
Jean-Pierre
JP
Mikol
Vincent
V
D000284:Administration, Oral; D000818:Animals; D001372:Aza Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001682:Biological Availability; D018360:Crystallography, X-Ray; D004285:Dogs; D065427:Factor Xa Inhibitors; D066298:In Vitro Techniques; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008024:Ligands; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D010879:Piperazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D015842:Serine Proteinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
D001372:Aza Compounds; D065427:Factor Xa Inhibitors; D007211:Indoles; D008024:Ligands; D010879:Piperazines; C472566:RPR 209685; D015842:Serine Proteinase Inhibitors; D013449:Sulfonamides