title: L-374,087, an efficacious, orally bioavailable, pyridinone acetamide thrombin inhibitor.
abstract: Replacement of the amidinopiperidine P1 group of 3-benzylsulfonylamino-6-methyl-2-pyridinone acetamide thrombin inhibitor L-373,890 (2) with a mildly basic 5-linked 2-amino-6-methylpyridine results in an equipotent compound L-374,087 (5, Ki = 0.5 nM). Compound 5 is highly selective for thrombin over trypsin, is efficacious in the rat ferric chloride model of arterial thrombosis and is orally bioavailable in dogs and cynomolgus monkeys. The structural basis for the critical importance of both methyl groups in 5 was confirmed by X-ray crystallography.
authors.affiliation: Department of Biological Chemistry, Merck Research Laboratories, West Point, PA 19486, USA.
authors.forename: P E
authors.initials: PE
authors.lastname: Sanderson
authors.forename: K J
authors.initials: KJ
authors.lastname: Cutrona
authors.forename: B D
authors.initials: BD
authors.lastname: Dorsey
authors.forename: D L
authors.initials: DL
authors.lastname: Dyer
authors.forename: C M
authors.initials: CM
authors.lastname: McDonough
authors.forename: A M
authors.initials: AM
authors.lastname: Naylor-Olsen
authors.forename: I W
authors.initials: IW
authors.lastname: Chen
authors.forename: Z
authors.initials: Z
authors.lastname: Chen
authors.forename: J J
authors.initials: JJ
authors.lastname: Cook
authors.forename: S J
authors.initials: SJ
authors.lastname: Gardell
authors.forename: J A
authors.initials: JA
authors.lastname: Krueger
authors.forename: S D
authors.initials: SD
authors.lastname: Lewis
authors.forename: J H
authors.initials: JH
authors.lastname: Lin
authors.forename: B J
authors.initials: BJ
authors.lastname: Lucas
authors.forename: E A
authors.initials: EA
authors.lastname: Lyle
authors.forename: J J
authors.initials: JJ
authors.lastname: Lynch
authors.forename: M T
authors.initials: MT
authors.lastname: Stranieri
authors.forename: K
authors.initials: K
authors.lastname: Vastag
authors.forename: J A
authors.initials: JA
authors.lastname: Shafer
authors.forename: J P
authors.initials: JP
authors.lastname: Vacca
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000925:Anticoagulants / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D001682:Biological Availability; D002712:Chlorides; D018360:Crystallography, X-Ray; D004285:Dogs; D005290:Ferric Compounds; D007700:Kinetics; D008252:Macaca fascicularis; D008958:Models, Molecular; D015394:Molecular Structure; D011728:Pyridones / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D013917:Thrombin / Q000037:antagonists & inhibitors*; D013927:Thrombosis / Q000188:drug therapy; D014357:Trypsin / Q000378:metabolism
chemical_list: D000925:Anticoagulants; D002712:Chlorides; D005290:Ferric Compounds; C116625:L 373890; C116624:L 374087; D011728:Pyridones; D013449:Sulfonamides; D014357:Trypsin; D013917:Thrombin; C024555:ferric chloride