title: Discovery of an orally efficacious inhibitor of coagulation factor Xa which incorporates a neutral P1 ligand.
abstract: 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.
authors.affiliation: Department of Medicinal Chemistry and Department of Biology, Aventis Pharmaceuticals, Route 202-206, Bridgewater, New Jersey 08807-0800, USA. yong-mi.choi@aventis.com
authors.forename: Yong Mi
authors.initials: YM
authors.lastname: Choi-Sledeski
authors.forename: Robert
authors.initials: R
authors.lastname: Kearney
authors.forename: Gregory
authors.initials: G
authors.lastname: Poli
authors.forename: Henry
authors.initials: H
authors.lastname: Pauls
authors.forename: Charles
authors.initials: C
authors.lastname: Gardner
authors.forename: Yong
authors.initials: Y
authors.lastname: Gong
authors.forename: Michael
authors.initials: M
authors.lastname: Becker
authors.forename: Roderick
authors.initials: R
authors.lastname: Davis
authors.forename: Alfred
authors.initials: A
authors.lastname: Spada
authors.forename: Guyan
authors.initials: G
authors.lastname: Liang
authors.forename: Valeria
authors.initials: V
authors.lastname: Chu
authors.forename: Karen
authors.initials: K
authors.lastname: Brown
authors.forename: Dennis
authors.initials: D
authors.lastname: Collussi
authors.forename: Robert
authors.initials: R
authors.lastname: Leadley
authors.forename: Sam
authors.initials: S
authors.lastname: Rebello
authors.forename: Phillip
authors.initials: P
authors.lastname: Moxey
authors.forename: Suzanne
authors.initials: S
authors.lastname: Morgan
authors.forename: Ross
authors.initials: R
authors.lastname: Bentley
authors.forename: Charles
authors.initials: C
authors.lastname: Kasiewski
authors.forename: Sebastien
authors.initials: S
authors.lastname: Maignan
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Guilloteau
authors.forename: Vincent
authors.initials: V
authors.lastname: Mikol
mesh_terms: 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
chemical_list: D001372:Aza Compounds; D065427:Factor Xa Inhibitors; D007211:Indoles; D008024:Ligands; D010879:Piperazines; C472566:RPR 209685; D015842:Serine Proteinase Inhibitors; D013449:Sulfonamides