title: Design, synthesis and biological activity of novel non-amidine factor Xa inhibitors. Part 1: P(1) structure-activity relationships of the substituted 1-(2-Naphthyl)-1H-pyrazole-5-carboxylamides.
abstract: Based on DuPont Pharmaceuticals' monobenzamidine lead structure SN429, we have designed the biphenyl 1-(2-naphthyl)-1H-pyrazole-5-carboxylamides as a novel series of non-basic factor Xa inhibitors. We have discovered that the displacement of the benzamidine moiety with substituted 2-naphthyl structures not only results in highly potent factor Xa inhibitors, but also significantly increases their enzyme specificity and oral bioavailability.
authors.affiliation: Medicinal Chemistry Department, Millennium Pharmaceuticals, Inc., 256 East Grand Ave, South San Francisco, CA 94080, USA. zhaozhong.jia@mpi.com
authors.forename: Zhaozhong J
authors.initials: ZJ
authors.lastname: Jia
authors.forename: Yanhong
authors.initials: Y
authors.lastname: Wu
authors.forename: Wenrong
authors.initials: W
authors.lastname: Huang
authors.forename: Erick
authors.initials: E
authors.lastname: Goldman
authors.forename: Penglie
authors.initials: P
authors.lastname: Zhang
authors.forename: John
authors.initials: J
authors.lastname: Woolfrey
authors.forename: Paul
authors.initials: P
authors.lastname: Wong
authors.forename: Brian
authors.initials: B
authors.lastname: Huang
authors.forename: Uma
authors.initials: U
authors.lastname: Sinha
authors.forename: Gary
authors.initials: G
authors.lastname: Park
authors.forename: Andrea
authors.initials: A
authors.lastname: Reed
authors.forename: Robert M
authors.initials: RM
authors.lastname: Scarborough
authors.forename: Bing-Yan
authors.initials: BY
authors.lastname: Zhu
mesh_terms: D000577:Amides / Q000737:chemistry; D000818:Animals; D015195:Drug Design; D065427:Factor Xa Inhibitors; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D015842:Serine Proteinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000577:Amides; D065427:Factor Xa Inhibitors; D011720:Pyrazoles; D015842:Serine Proteinase Inhibitors