title: P2 pyridine N-oxide thrombin inhibitors: a novel peptidomimetic scaffold.
abstract: In this study, we have demonstrated that the critical hydrogen bonding motif of the established 3-aminopyrazinone thrombin inhibitors can be effectively mimicked by a 2-aminopyridine N-oxide. As this peptidomimetic core is more resistant toward oxidative metabolism, it also overcomes the metabolic liability associated with the pyrazinones. An optimization study of the P(1) benzylamide delivered the potent thrombin inhibitor 21 (K(i) = 3.2 nM, 2xaPTT = 360 nM), which exhibited good plasma levels and half-life after oral dosing in the dog (C(max) = 2.6 microM, t(1/2) = 4.5 h).
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486, USA. philippe_nantermet@merck.com
authors.forename: Philippe G
authors.initials: PG
authors.lastname: Nantermet
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Burgey
authors.forename: Kyle A
authors.initials: KA
authors.lastname: Robinson
authors.forename: Janetta M
authors.initials: JM
authors.lastname: Pellicore
authors.forename: Christina L
authors.initials: CL
authors.lastname: Newton
authors.forename: James Z
authors.initials: JZ
authors.lastname: Deng
authors.forename: Harold G
authors.initials: HG
authors.lastname: Selnick
authors.forename: S Dale
authors.initials: SD
authors.lastname: Lewis
authors.forename: Bobby J
authors.initials: BJ
authors.lastname: Lucas
authors.forename: Julie A
authors.initials: JA
authors.lastname: Krueger
authors.forename: Cynthia
authors.initials: C
authors.lastname: Miller-Stein
authors.forename: Rebecca B
authors.initials: RB
authors.lastname: White
authors.forename: Bradley
authors.initials: B
authors.lastname: Wong
authors.forename: Daniel R
authors.initials: DR
authors.lastname: McMasters
authors.forename: Audrey A
authors.initials: AA
authors.lastname: Wallace
authors.forename: Joseph J
authors.initials: JJ
authors.lastname: Lynch
authors.forename: Youwei
authors.initials: Y
authors.lastname: Yan
authors.forename: Zhongguo
authors.initials: Z
authors.lastname: Chen
authors.forename: Lawrence
authors.initials: L
authors.lastname: Kuo
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Gardell
authors.forename: Jules A
authors.initials: JA
authors.lastname: Shafer
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Vacca
authors.forename: Terry A
authors.initials: TA
authors.lastname: Lyle
mesh_terms: D000991:Antithrombins / Q000737:chemistry*; D006860:Hydrogen Bonding; D008958:Models, Molecular; D018716:Molecular Mimicry; D011743:Pyrimidines / Q000737:chemistry*
chemical_list: D000991:Antithrombins; D011743:Pyrimidines