title: P3 optimization of functional potency, in vivo efficacy and oral bioavailability in 3-aminopyrazinone thrombin inhibitors bearing non-charged groups at the P1 position.
abstract: Although the S3 pocket of the thrombin active site is lined with lipophilic amino acid residues, the accommodation of polarity within the lipophilic P3 moiety of small molecule inhibitors is possible provided that the polar functionality is capable of pointing away from the binding pocket outwards toward solvent while simultaneously allowing the lipophilic portion of the P3 ligand to interact with the S3 amino acid residues. Manipulation of this motif provided the means to effect optimization of functional potency, in vivo antithrombotic efficacy and oral bioavailability in a series of 3-aminopyrazinone thrombin inhibitors which contained non-charged groups at the P1 position.
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486, USA. richard_isaacs@verizon.net
authors.forename: Richard C A
authors.initials: RC
authors.lastname: Isaacs
authors.forename: Christina L
authors.initials: CL
authors.lastname: Newton
authors.forename: Kellie J
authors.initials: KJ
authors.lastname: Cutrona
authors.forename: Swati P
authors.initials: SP
authors.lastname: Mercer
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Dorsey
authors.forename: Colleen M
authors.initials: CM
authors.lastname: McDonough
authors.forename: Jacquelynn J
authors.initials: JJ
authors.lastname: Cook
authors.forename: Julie A
authors.initials: JA
authors.lastname: Krueger
authors.forename: S Dale
authors.initials: SD
authors.lastname: Lewis
authors.forename: Bobby J
authors.initials: BJ
authors.lastname: Lucas
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Lyle
authors.forename: Joseph J
authors.initials: JJ
authors.lastname: Lynch
authors.forename: Cynthia
authors.initials: C
authors.lastname: Miller-Stein
authors.forename: Maria T
authors.initials: MT
authors.lastname: Michener
authors.forename: Audrey A
authors.initials: AA
authors.lastname: Wallace
authors.forename: Rebecca B
authors.initials: RB
authors.lastname: White
authors.forename: Bradley K
authors.initials: BK
authors.lastname: Wong
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000925:Anticoagulants / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D001682:Biological Availability; D001778:Blood Coagulation Disorders / Q000188:drug therapy*; D004285:Dogs; D015195:Drug Design; D015394:Molecular Structure; D011719:Pyrazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship; D013917:Thrombin / Q000037:antagonists & inhibitors*
chemical_list: C482960:3-aminopyrazinone; D000925:Anticoagulants; D011719:Pyrazines; D013917:Thrombin