3CS7

FACTOR XA IN COMPLEX WITH THE INHIBITOR 1-(4-methoxyphenyl)-6-(4-(1-(pyrrolidin-1-ylmethyl)cyclopropyl)phenyl)-3-(trifluoromethyl)-5,6-dihydro-1H-pyrazolo[3,4-c]pyridin-7(4H)-one

Summary for 3CS7

• Entry DOI: 10.2210/pdb3cs7/pdb
• Descriptor: Coagulation factor X, CALCIUM ION, 1-(4-methoxyphenyl)-6-(4-(1-(pyrrolidin-1-ylmethyl)cyclopropyl)phenyl)-3-(trifluoromethyl)-5,6-dihydro-1H-pyrazolo[3,4-c]pyridin-7(4H)-one, ... (5 entities in total)
• Functional Keywords: glycoprotein, hydrolase, serine protease, plasma, blood coagulation factor, protein inhibitor complex, calcium-binding, cleavage on pair of basic residues, egf-like domain, gamma-carboxyglutamic acid, hydroxylation, polymorphism, zymogen, blood coagulation, calcium, protease
• Biological source: Homo sapiens (Human); More
• Cellular location: Secreted: P00742 P00742
• Total number of polymer chains: 2
• Total formula weight: 32586.97

Authors

Alexander, R.S. (deposition date: 2008-04-09, release date: 2008-07-08, Last modification date: 2024-10-09)

Primary citation

Qiao, J.X.,Cheney, D.L.,Alexander, R.S.,Smallwood, A.M.,King, S.R.,He, K.,Rendina, A.R.,Luettgen, J.M.,Knabb, R.M.,Wexler, R.R.,Lam, P.Y.
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.
Bioorg.Med.Chem.Lett., 18:4118-4123, 2008

PubMed Abstract: 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.

PubMed: 18550370
DOI: 10.1016/j.bmcl.2008.05.095

Experimental method

X-RAY DIFFRACTION (2.2 Å)