title: Metabolism-directed optimization of 3-aminopyrazinone acetamide thrombin inhibitors. Development of an orally bioavailable series containing P1 and P3 pyridines.
abstract: Recent efforts in the field of thrombin inhibitor research have focused on the identification of compounds with good oral bioavailability and pharmacokinetics. In this manuscript we describe a metabolism-based approach to the optimization of the 3-(2-phenethylamino)-6-methylpyrazinone acetamide template (e.g., 1) which resulted in the modification of each of the three principal components (i.e., P1, P2, P3) comprising this series. As a result of these studies, several potent thrombin inhibitors (e.g., 20, 24, 25) were identified which exhibit high levels of oral bioavailability and long plasma half-lives.
authors.affiliation: Departments of Medicinal Chemistry, Biological Chemistry, Drug Metabolism, Molecular Systems, Structural Biology, and Pharmacology, Merck Research Laboratories, West Point, Pennsylvania 19486, USA. christopher_burgey@merck.com
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Burgey
authors.forename: Kyle A
authors.initials: KA
authors.lastname: Robinson
authors.forename: Terry A
authors.initials: TA
authors.lastname: Lyle
authors.forename: Philip E J
authors.initials: PE
authors.lastname: Sanderson
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: Rominder
authors.initials: R
authors.lastname: Singh
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: Elizabeth A
authors.initials: EA
authors.lastname: Lyle
authors.forename: Peter D
authors.initials: PD
authors.lastname: Williams
authors.forename: Craig A
authors.initials: CA
authors.lastname: Coburn
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Dorsey
authors.forename: James C
authors.initials: JC
authors.lastname: Barrow
authors.forename: Maria T
authors.initials: MT
authors.lastname: Stranieri
authors.forename: Marie A
authors.initials: MA
authors.lastname: Holahan
authors.forename: Gary R
authors.initials: GR
authors.lastname: Sitko
authors.forename: Jacquelynn J
authors.initials: JJ
authors.lastname: Cook
authors.forename: Daniel R
authors.initials: DR
authors.lastname: McMasters
authors.forename: Colleen M
authors.initials: CM
authors.lastname: McDonough
authors.forename: William M
authors.initials: WM
authors.lastname: Sanders
authors.forename: Audrey A
authors.initials: AA
authors.lastname: Wallace
authors.forename: Franklin C
authors.initials: FC
authors.lastname: Clayton
authors.forename: Dennis
authors.initials: D
authors.lastname: Bohn
authors.forename: Yvonne M
authors.initials: YM
authors.lastname: Leonard
authors.forename: Theodore J
authors.initials: TJ
authors.lastname: Detwiler
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
mesh_terms: D000081:Acetamides / Q000138:chemical synthesis / Q000493:pharmacokinetics* / Q000494:pharmacology; D000284:Administration, Oral; D000818:Animals; D000925:Anticoagulants / Q000138:chemical synthesis / Q000493:pharmacokinetics* / Q000494:pharmacology; D001682:Biological Availability; D018360:Crystallography, X-Ray; D004285:Dogs; D008253:Macaca mulatta; D008958:Models, Molecular; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011719:Pyrazines / Q000138:chemical synthesis / Q000493:pharmacokinetics* / Q000494:pharmacology; D011725:Pyridines / Q000138:chemical synthesis / Q000493:pharmacokinetics* / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship; D013917:Thrombin / Q000037:antagonists & inhibitors*
chemical_list: D000081:Acetamides; D000925:Anticoagulants; D011480:Protease Inhibitors; D011719:Pyrazines; D011725:Pyridines; D013917:Thrombin