title: Efficacious, orally bioavailable thrombin inhibitors based on 3-aminopyridinone or 3-aminopyrazinone acetamide peptidomimetic templates.
abstract: We have addressed the key deficiency of noncovalent pyridinone acetamide thrombin inhibitor L-374,087 (1), namely, its modest half-lives in animals, by making a chemically stable 3-alkylaminopyrazinone bioisostere for its 3-sulfonylaminopyridinone core. Compound 3 (L-375,378), the closest aminopyrazinone analogue of 1, has comparable selectivity and slightly decreased efficacy but significantly improved pharmacokinetics in rats, dogs, and monkeys to 1. We have developed an efficient and versatile synthesis of 3, and this compound has been chosen for further preclinical and clinical development.
authors.affiliation: Departments of Antiviral Research, Biological Chemistry, Drug Metabolism, Medicinal Chemistry, Molecular Design and Diversity, Pharmacology, Merck Research Laboratories, West Point, Pennsylvania 19486, USA.
authors.forename: P E
authors.initials: PE
authors.lastname: Sanderson
authors.forename: T A
authors.initials: TA
authors.lastname: Lyle
authors.forename: K J
authors.initials: KJ
authors.lastname: Cutrona
authors.forename: D L
authors.initials: DL
authors.lastname: Dyer
authors.forename: B D
authors.initials: BD
authors.lastname: Dorsey
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: C M
authors.initials: CM
authors.lastname: Cooper
authors.forename: S J
authors.initials: SJ
authors.lastname: Gardell
authors.forename: T R
authors.initials: TR
authors.lastname: Hare
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: Y
authors.initials: Y
authors.lastname: Yan
authors.forename: J A
authors.initials: JA
authors.lastname: Shafer
authors.forename: J P
authors.initials: JP
authors.lastname: Vacca
mesh_terms: D000631:Aminopyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D001682:Biological Availability; D018360:Crystallography, X-Ray; D004285:Dogs; D008253:Macaca mulatta; D008958:Models, Molecular; D018716:Molecular Mimicry; D010455:Peptides / Q000737:chemistry*; D011719:Pyrazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D011728:Pyridones / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship; D013917:Thrombin / Q000037:antagonists & inhibitors*
chemical_list: D000631:Aminopyridines; C115582:L 375378; D010455:Peptides; D011719:Pyrazines; D011728:Pyridones; D013917:Thrombin