title: Design of novel, potent, noncovalent inhibitors of thrombin with nonbasic P-1 substructures: rapid structure-activity studies by solid-phase synthesis.
abstract: Study of surface representations of the inhibitor-bound thrombin P-1 pocket revealed a lipophilic recess in this pocket which is not occupied by any known inhibitor. Solid-phase synthesis was used to generate benzylamides of D-diphenylAlaPro by aminolysis of Boc dipeptide Kaiser resin. The resulting amides inhibited thrombin in the range IC50 = 3-13,000 nM, and the structure-activity relationships and molecular modeling suggest a unique fit of the benzyl side chain into P-1 with the meta substituent occupying the recess.
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, West Point, Pennsylvania 19486, USA.
authors.forename: W C
authors.initials: WC
authors.lastname: Lumma
authors.forename: K M
authors.initials: KM
authors.lastname: Witherup
authors.forename: T J
authors.initials: TJ
authors.lastname: Tucker
authors.forename: S F
authors.initials: SF
authors.lastname: Brady
authors.forename: J T
authors.initials: JT
authors.lastname: Sisko
authors.forename: A M
authors.initials: AM
authors.lastname: Naylor-Olsen
authors.forename: S D
authors.initials: SD
authors.lastname: Lewis
authors.forename: B J
authors.initials: BJ
authors.lastname: Lucas
authors.forename: J P
authors.initials: JP
authors.lastname: Vacca
mesh_terms: D000991:Antithrombins / Q000138:chemical synthesis* / Q000737:chemistry; D001559:Benzhydryl Compounds / Q000138:chemical synthesis* / Q000737:chemistry; D015195:Drug Design; D008958:Models, Molecular; D011758:Pyrroles / Q000138:chemical synthesis* / Q000737:chemistry; D013329:Structure-Activity Relationship; D013917:Thrombin / Q000037:antagonists & inhibitors*
chemical_list: D000991:Antithrombins; D001559:Benzhydryl Compounds; C111675:L 373722; C111674:L 377009; D011758:Pyrroles; D013917:Thrombin