title: SAR and X-ray structures of enantiopure 1,2-cis-(1R,2S)-cyclopentyldiamine and cyclohexyldiamine derivatives as inhibitors of coagulation Factor Xa.
abstract: In the search of Factor Xa (FXa) inhibitors structurally different from the pyrazole-based series, we identified a viable series of enantiopure cis-(1R,2S)-cycloalkyldiamine derivatives as potent and selective inhibitors of FXa. Among them, cyclohexyldiamide 7 and cyclopentyldiamide 9 were the most potent neutral compounds, and had good anticoagulant activity comparable to the pyrazole-based analogs. Crystal structures of 7-FXa and 9-FXa illustrate binding similarities and differences between the five- and the six-membered core systems, and provide rationales for the observed SAR of P1 and linker moieties.
authors.affiliation: Bristol-Myers Squibb Company, Research and Development, PO Box 5400, Princeton, NJ 08543-5400, USA. jennifer.qiao@bms.com
authors.forename: Jennifer X
authors.initials: JX
authors.lastname: Qiao
authors.forename: Chong-Hwan
authors.initials: CH
authors.lastname: Chang
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Cheney
authors.forename: Paul E
authors.initials: PE
authors.lastname: Morin
authors.forename: Gren Z
authors.initials: GZ
authors.lastname: Wang
authors.forename: Sarah R
authors.initials: SR
authors.lastname: King
authors.forename: Tammy C
authors.initials: TC
authors.lastname: Wang
authors.forename: Alan R
authors.initials: AR
authors.lastname: Rendina
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Luettgen
authors.forename: Robert M
authors.initials: RM
authors.lastname: Knabb
authors.forename: Ruth R
authors.initials: RR
authors.lastname: Wexler
authors.forename: Patrick Y S
authors.initials: PY
authors.lastname: Lam
mesh_terms: D000925:Anticoagulants / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D003959:Diamines / Q000737:chemistry* / Q000494:pharmacology*; D065427:Factor Xa Inhibitors; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D011517:Prothrombin Time; D013329:Structure-Activity Relationship; D014961:X-Ray Diffraction
chemical_list: D000925:Anticoagulants; D003959:Diamines; D065427:Factor Xa Inhibitors