Achieving structural diversity using the perpendicular conformation of alpha-substituted phenylcyclopropanes to mimic the bioactive conformation of ortho-substituted biphenyl P4 moieties: discovery of novel, highly potent inhibitors of Factor Xa.
Ortho-substituted biphenyl moieties are widely used in drug design. We herein report a successful use of the perpendicular conformation of the alpha-substituted phenylcyclopropyl groups to mimic the aplanar, biologically active conformation of the ortho-substituted biphenyl moieties to achieve structural diversity. This is exemplified by the design and synthesis of a series of highly potent pyrazole bicyclic-based Factor Xa (FXa) inhibitors bearing alpha-substituted phenylcyclopropyl P4 moieties. The designed perpendicular conformation was confirmed by the X-ray structure of FXa-bound compound 2r. The potential structural basis for the high FXa potency in the phenylcyclopropyl P4 analogs and their improved FXa inhibitory activities compared with the biphenyl P4 counterparts are discussed.
Bristol-Myers Squibb Company, Research and Development, PO Box 5400, Princeton, NJ 08543-5400, USA. jennifer.qiao@bms.com
Jennifer X
JX
Qiao
Daniel L
DL
Cheney
Richard S
RS
Alexander
Angela M
AM
Smallwood
Sarah R
SR
King
Kan
K
He
Alan R
AR
Rendina
Joseph M
JM
Luettgen
Robert M
RM
Knabb
Ruth R
RR
Wexler
Patrick Y S
PY
Lam
D001665:Binding Sites; D001713:Biphenyl Compounds / Q000737:chemistry*; D001777:Blood Coagulation / Q000187:drug effects; D045744:Cell Line, Tumor; D002626:Chemistry, Pharmaceutical / Q000379:methods; D003521:Cyclopropanes / Q000737:chemistry*; D015195:Drug Design; D004583:Electrons; D015951:Factor Xa / Q000737:chemistry*; D065427:Factor Xa Inhibitors; D006801:Humans; D007700:Kinetics; D008956:Models, Chemical; D008958:Models, Molecular; D008968:Molecular Conformation; D013927:Thrombosis / Q000188:drug therapy
D001713:Biphenyl Compounds; D003521:Cyclopropanes; D015951:Factor Xa; D065427:Factor Xa Inhibitors; C010574:biphenyl