SAR and X-ray structures of enantiopure 1,2-cis-(1R,2S)-cyclopentyldiamine and cyclohexyldiamine derivatives as inhibitors of coagulation Factor Xa.
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.
Qiao
Jennifer X
JX
Bristol-Myers Squibb Company, Research and Development, PO Box 5400, Princeton, NJ 08543-5400, USA. jennifer.qiao@bms.com
Chang
Chong-Hwan
CH
Cheney
Daniel L
DL
Morin
Paul E
PE
Wang
Gren Z
GZ
King
Sarah R
SR
Wang
Tammy C
TC
Rendina
Alan R
AR
Luettgen
Joseph M
JM
Knabb
Robert M
RM
Wexler
Ruth R
RR
Lam
Patrick Y S
PY
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
D000925:Anticoagulants; D003959:Diamines; D065427:Factor Xa Inhibitors