title: Discovery of a novel, selective, and orally bioavailable class of thrombin inhibitors incorporating aminopyridyl moieties at the P1 position.
abstract: A novel class of thrombin inhibitors incorporating aminopyridyl moieties at the P1 position has been discovered. Four of these thrombin inhibitors (13b,c,e and 14d) showed nanomolar potency (Ki 0.8-12 nM), 300-1500-fold selectivity for thrombin compared with trypsin, and good oral bioavailability (F = 40-76%) in rats or dogs. The neutral P1 was expected to increase metabolic stability and oral absorption. Identification of this novel aminopyridyl group at P1 was a key step in our search for a clinical candidate.
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, West Point, Pennsylvania 19486, USA.
authors.forename: D M
authors.initials: DM
authors.lastname: Feng
authors.forename: S J
authors.initials: SJ
authors.lastname: Gardell
authors.forename: S D
authors.initials: SD
authors.lastname: Lewis
authors.forename: M G
authors.initials: MG
authors.lastname: Bock
authors.forename: Z
authors.initials: Z
authors.lastname: Chen
authors.forename: R M
authors.initials: RM
authors.lastname: Freidinger
authors.forename: A M
authors.initials: AM
authors.lastname: Naylor-Olsen
authors.forename: H G
authors.initials: HG
authors.lastname: Ramjit
authors.forename: R
authors.initials: R
authors.lastname: Woltmann
authors.forename: E P
authors.initials: EP
authors.lastname: Baskin
authors.forename: J J
authors.initials: JJ
authors.lastname: Lynch
authors.forename: R
authors.initials: R
authors.lastname: Lucas
authors.forename: J A
authors.initials: JA
authors.lastname: Shafer
authors.forename: K B
authors.initials: KB
authors.lastname: Dancheck
authors.forename: I W
authors.initials: IW
authors.lastname: Chen
authors.forename: S S
authors.initials: SS
authors.lastname: Mao
authors.forename: J A
authors.initials: JA
authors.lastname: Krueger
authors.forename: T R
authors.initials: TR
authors.lastname: Hare
authors.forename: A M
authors.initials: AM
authors.lastname: Mulichak
authors.forename: J P
authors.initials: JP
authors.lastname: Vacca
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000991:Antithrombins / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D001682:Biological Availability; D018360:Crystallography, X-Ray; D004151:Dipeptides / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D004285:Dogs; D007700:Kinetics; D011725:Pyridines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship; D013917:Thrombin / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000991:Antithrombins; D004151:Dipeptides; D011725:Pyridines; D013917:Thrombin