title: Pharmacokinetic optimization of 3-amino-6-chloropyrazinone acetamide thrombin inhibitors. Implementation of P3 pyridine N-oxides to deliver an orally bioavailable series containing P1 N-benzylamides.
abstract: In this manuscript we demonstrate that a modification principally directed toward the improvement of the aqueous solubility (i.e., introduction a P3 pyridine N-oxide) of the previous lead compound afforded a new series of potent orally bioavailable P1 N-benzylamide thrombin inhibitors. An expedited investigation of the P1 SAR with respect to oral bioavailability, plasma half-life, and human liver microsome stability revealed 5 as the best candidate for advanced evaluation.
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486, USA. christopher_urgey@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: Philippe G
authors.initials: PG
authors.lastname: Nantermet
authors.forename: Harold G
authors.initials: HG
authors.lastname: Selnick
authors.forename: Richard C A
authors.initials: RC
authors.lastname: Isaacs
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: Maria T
authors.initials: MT
authors.lastname: Stranieri
authors.forename: Jacquelynn J
authors.initials: JJ
authors.lastname: Cook
authors.forename: Daniel R
authors.initials: DR
authors.lastname: McMasters
authors.forename: Janetta M
authors.initials: JM
authors.lastname: Pellicore
authors.forename: Swati
authors.initials: S
authors.lastname: Pal
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: Denise C
authors.initials: DC
authors.lastname: Welsh
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* / Q000494:pharmacology*; D000818:Animals; D001682:Biological Availability; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D018360:Crystallography, X-Ray; D004285:Dogs; D006207:Half-Life; D006801:Humans; D066298:In Vitro Techniques; D007275:Injections, Intravenous; D008253:Macaca mulatta; D008862:Microsomes, Liver / Q000378:metabolism; D008958:Models, Molecular; D010087:Oxides / Q000737:chemistry; D011719:Pyrazines / Q000138:chemical synthesis* / Q000494:pharmacology*; D011725:Pyridines / Q000737:chemistry*; D051381:Rats; D012995:Solubility; D013329:Structure-Activity Relationship; D013917:Thrombin / Q000037:antagonists & inhibitors*; D013927:Thrombosis / Q000139:chemically induced / Q000188:drug therapy
chemical_list: C478338:3-amino-6-chloropyrazinone acetamide; D000081:Acetamides; D010087:Oxides; D011719:Pyrazines; D011725:Pyridines; D013917:Thrombin