title: Design, parallel synthesis, and crystal structures of biphenyl antithrombotics as selective inhibitors of tissue factor FVIIa complex. Part 1: Exploration of S2 pocket pharmacophores.
abstract: Factor VIIa (FVIIa), a serine protease enzyme, coupled with tissue factor (TF) plays an important role in a number of thrombosis-related disorders. Inhibition of TF x FVIIa occurs early in the coagulation cascade and might provide some safety advantages over other related enzymes. We report here a novel series of substituted biphenyl derivatives that are highly potent and selective TF x FVIIa inhibitors. Parallel synthesis coupled with structure-based drug design allowed us to explore the S2 pocket of the enzyme active site. A number of compounds with IC(50) value of <10 nM were synthesized. The X-ray crystal structures of some of these compounds complexed with TF x FVIIa were determined and results were applied to design the next round of inhibitors. All the potent inhibitors were tested for inhibition against a panel of related enzymes and selectivity of 17,600 over thrombin, 450 over trypsin, 685 over FXa, and 76 over plasmin was achieved. Two groups, vinyl 36b and 2-furan 36ab, were identified as the optimum binding substituents on the phenyl ring in the S2 pocket. Compounds with these two substituents are the most potent compounds in this series with good selectivity over related serine proteases. These compounds will be further explored for structure-activity relationship.
authors.affiliation: BioCryst Pharmaceuticals, Inc., 2190 Parkway Lake Drive, Birmingham, AL 35244, USA. pkotian@biocryst.com
authors.forename: Pravin L
authors.initials: PL
authors.lastname: Kotian
authors.forename: Raman
authors.initials: R
authors.lastname: Krishnan
authors.forename: Scott
authors.initials: S
authors.lastname: Rowland
authors.forename: Yahya
authors.initials: Y
authors.lastname: El-Kattan
authors.forename: Surendra K
authors.initials: SK
authors.lastname: Saini
authors.forename: Ramanda
authors.initials: R
authors.lastname: Upshaw
authors.forename: Shanta
authors.initials: S
authors.lastname: Bantia
authors.forename: Shane
authors.initials: S
authors.lastname: Arnold
authors.forename: Y Sudhakar
authors.initials: YS
authors.lastname: Babu
authors.forename: Pooran
authors.initials: P
authors.lastname: Chand
mesh_terms: D000925:Anticoagulants / Q000737:chemistry* / Q000494:pharmacology*; D001665:Binding Sites; D001713:Biphenyl Compounds / Q000737:chemistry / Q000494:pharmacology; D001777:Blood Coagulation / Q000187:drug effects*; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D015195:Drug Design; D015942:Factor VIIa / Q000037:antagonists & inhibitors*; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D015394:Molecular Structure; D013329:Structure-Activity Relationship
chemical_list: D000925:Anticoagulants; D001713:Biphenyl Compounds; D015942:Factor VIIa; C010574:biphenyl