title: Discovery and evaluation of potent P1 aryl heterocycle-based thrombin inhibitors.
abstract: In an effort to discover potent, clinically useful thrombin inhibitors, a rapid analogue synthetic approach was used to explore the P(1) region. Various benzylamines were coupled to a pyridine/pyrazinone P(2)-P(3) template. One compound with an o-thiadiazole benzylic substitution was found to have a thrombin K(i) of 0.84 nM. A study of ortho-substituted five-membered-ring heterocycles was undertaken and subsequently demonstrated that the o-triazole and tetrazole rings were optimal. Combination of these potent P(1) aryl heterocycles with a variety of P(2)-P(3) groups produced a compound with an extraordinary thrombin inhibitory activity of 1.4 pM. It is hoped that this potency enhancement in P(1) will allow for more diversification in the P(2)-P(3) region to ultimately address additional pharmacological concerns.
authors.affiliation: Medicinal Chemistry, Merck Research Laboratories, Merck and Co., Inc., WP14-3, Post Office Box 4, Sumneytown Pike, West Point, PA 19486, USA. mary_beth_young@merck.com
authors.forename: Mary Beth
authors.initials: MB
authors.lastname: Young
authors.forename: James C
authors.initials: JC
authors.lastname: Barrow
authors.forename: Kristen L
authors.initials: KL
authors.lastname: Glass
authors.forename: George F
authors.initials: GF
authors.lastname: Lundell
authors.forename: Christina L
authors.initials: CL
authors.lastname: Newton
authors.forename: Janetta M
authors.initials: JM
authors.lastname: Pellicore
authors.forename: Kenneth E
authors.initials: KE
authors.lastname: Rittle
authors.forename: Harold G
authors.initials: HG
authors.lastname: Selnick
authors.forename: Kenneth J
authors.initials: KJ
authors.lastname: Stauffer
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Vacca
authors.forename: Peter D
authors.initials: PD
authors.lastname: Williams
authors.forename: Dennis
authors.initials: D
authors.lastname: Bohn
authors.forename: Franklin C
authors.initials: FC
authors.lastname: Clayton
authors.forename: Jacquelynn J
authors.initials: JJ
authors.lastname: Cook
authors.forename: Julie A
authors.initials: JA
authors.lastname: Krueger
authors.forename: Lawrence C
authors.initials: LC
authors.lastname: Kuo
authors.forename: S Dale
authors.initials: SD
authors.lastname: Lewis
authors.forename: Bobby J
authors.initials: BJ
authors.lastname: Lucas
authors.forename: Daniel R
authors.initials: DR
authors.lastname: McMasters
authors.forename: Cynthia
authors.initials: C
authors.lastname: Miller-Stein
authors.forename: Beth L
authors.initials: BL
authors.lastname: Pietrak
authors.forename: Audrey A
authors.initials: AA
authors.lastname: Wallace
authors.forename: Rebecca B
authors.initials: RB
authors.lastname: White
authors.forename: Bradley
authors.initials: B
authors.lastname: Wong
authors.forename: Youwei
authors.initials: Y
authors.lastname: Yan
authors.forename: Philippe G
authors.initials: PG
authors.lastname: Nantermet
mesh_terms: D001596:Benzylamines / Q000138:chemical synthesis / Q000737:chemistry; D001665:Binding Sites; D006571:Heterocyclic Compounds / Q000138:chemical synthesis* / Q000737:chemistry; D008958:Models, Molecular; D011719:Pyrazines / Q000138:chemical synthesis / Q000737:chemistry; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry; D013329:Structure-Activity Relationship; D013777:Tetrazoles / Q000138:chemical synthesis / Q000737:chemistry; D013830:Thiadiazoles / Q000138:chemical synthesis / Q000737:chemistry; D013917:Thrombin / Q000037:antagonists & inhibitors* / Q000737:chemistry; D014230:Triazoles / Q000138:chemical synthesis / Q000737:chemistry
chemical_list: D001596:Benzylamines; D006571:Heterocyclic Compounds; D011719:Pyrazines; D011725:Pyridines; D013777:Tetrazoles; D013830:Thiadiazoles; D014230:Triazoles; D013917:Thrombin