Synthesis, characterization, and structure-activity relationships of amidine-substituted (bis)benzylidene-cycloketone olefin isomers as potent and selective factor Xa inhibitors

Journal of Medicinal Chemistry

Volumn 42, Issue 26, 1999, Pages 5415-5425

  Guilford, William J ^a   Shaw, Kenneth J ^a   Dallas, Jerry L ^a   Koovakkat, Sunil ^a   Lee, Wheeseong ^a   Liang, Amy ^a   Light, David R ^a   McCarrick, Margaret A ^a   Whitlow, Marc ^a   Ye, Bin ^a   Morrissey, Michael M ^a  

^a Discovery Research Group   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

2 [4 [(1 ACETIMIDOYL 3 PYRROLIDINYL)OXY]PHENYL] 3 (7 AMIDINO 2 NAPHTHYL)PROPIONIC ACID; 2,7 BIS(4 AMIDINOBENZYLEDENE)CYCLOHEPTAN 1 ONE; AMIDINE; BLOOD CLOTTING FACTOR 10A INHIBITOR; UNCLASSIFIED DRUG;

ARTICLE; BLOOD CLOTTING; CONTROLLED STUDY; DRUG ACTIVITY; DRUG POTENCY; DRUG SELECTIVITY; DRUG STRUCTURE; DRUG SYNTHESIS; ISOMER; STRUCTURE ACTIVITY RELATION;

BENZYLIDENE COMPOUNDS; FACTOR XA; HUMANS; MAGNETIC RESONANCE SPECTROSCOPY; SERINE PROTEINASE INHIBITORS; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 0033620012     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm990456v     Document Type: Article

References (42)

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2. A communication introducing this material has been published: Shaw, K. J.; Guilford, W. J.; Dallas, J. L.; Koovakaat, S. K.; McCarrick, M. A.; Liang, A.; Light, D. R.; Morrissey, M. M. (Z,Z)-2,7-Bis-(4-amidinobenzylidene)-cycloheptan-1-one: identification of a highly active inhibitor of blood coagulation factor Xa. J. Med. Chem. 1998, 41, 3551-3556.
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31. Prepared in a manner similar to 7.
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39. The AMBER program package was used for all molecular dynamics simulations (Case, D. A.; Pearlman, D. A; Caldwell, J. W.; Cheatham, T.E.; Ross, W. S.; Simmerling, C. L.; Darden, T. A.; Merz, K. M.; Stanton, R. V.; Cheng, A. L.; Vincent, J. J.; Crowley, M.; Ferguson, D. M.; Radmer, R. J.; Seibel, G. L.; Singh, U. C.; Weiner, P. K.; Kollman, P. A. AMBER 5; University of California: San Francisco, 1997) with the parm94 force field (Cornell, W. D.; Cieplak, P.; Bayly, C. I.; Gould, I. R.; Merz, K. M.; Ferguson, D. M.; Spellmeyer, D. C.; Fox, T.; Caldwell, J. W.; Kollman, P. A. A second generation force field for the simulation of proteins, nucleic acids, and organic molecules. J. Am. Chem. Soc. 1995, 117, 5179-5197.) Additional parameters were developed for the inhibitors (see ref 2). All simulations consisted of molecular dynamics of the active site region, inhibitor, and explicit solvent, with the remainder of the protein fixed. A time step of 0.002 ps was used with all bond lengths constrained to their equilibrium values. Simulations were either 200 ps or 500 ps in length, as noted in the text. A cutoff of 9.0 A was used for nonbonded interactions. The initial coordinates for thrombin and FXa were from the Brookhaven protein databank entries 1AHT and 1HCG, respectively.
40. The AMBER program package was used for all molecular dynamics simulations (Case, D. A.; Pearlman, D. A; Caldwell, J. W.; Cheatham, T.E.; Ross, W. S.; Simmerling, C. L.; Darden, T. A.; Merz, K. M.; Stanton, R. V.; Cheng, A. L.; Vincent, J. J.; Crowley, M.; Ferguson, D. M.; Radmer, R. J.; Seibel, G. L.; Singh, U. C.; Weiner, P. K.; Kollman, P. A. AMBER 5; University of California: San Francisco, 1997) with the parm94 force field (Cornell, W. D.; Cieplak, P.; Bayly, C. I.; Gould, I. R.; Merz, K. M.; Ferguson, D. M.; Spellmeyer, D. C.; Fox, T.; Caldwell, J. W.; Kollman, P. A. A second generation force field for the simulation of proteins, nucleic acids, and organic molecules. J. Am. Chem. Soc. 1995, 117, 5179-5197.) Additional parameters were developed for the inhibitors (see ref 2). All simulations consisted of molecular dynamics of the active site region, inhibitor, and explicit solvent, with the remainder of the protein fixed. A time step of 0.002 ps was used with all bond lengths constrained to their equilibrium values. Simulations were either 200 ps or 500 ps in length, as noted in the text. A cutoff of 9.0 A was used for nonbonded interactions. The initial coordinates for thrombin and FXa were from the Brookhaven protein databank entries 1AHT and 1HCG, respectively.
41. Katakura, S.; Nagahara, T.; Hara, T.; Iwamoto, M. A Novel Factor Xa Inhibitor: Structure-activity Relationships and Selectivity Between Factor Xa and Thrombin. Biochem. Biophys. Res. Commun. 1993, 197 (2), 965-972.
42. LogD calculations were performed using LogD Predictor Version 4.0 - demo from Advanced Chemistry Development Inc.