Derivatives of 5-amidine indole as inhibitors of thrombin catalytic activity

Bioorganic and Medicinal Chemistry Letters

Volumn 6, Issue 12, 1996, Pages 1339-1344

  Iwanowicz, Edwin J ^a   Lau, Wan F ^a   Lin, James ^a   Roberts, Daniel G M ^a   Seiler, Steven M ^a  

^a BRISTOL MYERS SQUIBB   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

AMIDINE; BMS 183507; SERINE PROTEINASE INHIBITOR; THROMBIN; THROMBIN INHIBITOR; UNCLASSIFIED DRUG;

ARTICLE; BLOOD CLOTTING; CRYSTAL STRUCTURE; DRUG BIOAVAILABILITY; DRUG DESIGN; DRUG HALF LIFE; DRUG POTENCY; DRUG TARGETING; ENZYME ACTIVITY; THROMBUS;

EID: 0029952180     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/0960-894X(96)00229-6     Document Type: Article

References (22)

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2. (b) Bagdy, D.; Barabas, Szabo, G.; E.; Bajusz, S.; Szell, E. Thrombosis and Haemostasis 1992, 67, 357.
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9. The coordinates of α-thrombin were taken from the structure of PPACK-α-thrombin (ref 6a). The molecular model of 1 was constructed using SYBYL (ref 13) and minimized with Macromodel/BatchMin (ref 14) and then docked using DGEOM (ref 15) with hydrogen bond distance contraints between the amidino terminus nitrogens and the carboxyl oxygens of Asp189. Fifty trial DGEOM structures were generated for 1. These were minimized in the active site of thrombin with BatchMin employing the AMBER (ref 16) united atom force field. The protein atoms were constrained with a harmonic constraint of 100 kJ/Å. The inhibitor was allowed to minimize without any constraints. The minimizations employed a distance dependent dielectric constant of 2r, the electrostatic cutoff was 12 Å, van der Waals cutoff was 7 Å, and the H-bonding cutoff was 4.0 Å. The results were visualized using SYBYL running on a Silicon Graphics 420VGX.
10. (a) Numbering of thrombin residues is based on that for chymotrypsin: Bode, W.; Mayr, I.; Baumann, U.; Huber, R.; Stone, S. R.; Hofsteenge, J. EMBO J. 1989, 8, 3467.
11. (b) Proximal and Distal pockets as used by: Banner, D. W.; Hadvary, P. J. Biol. Chem. 1991, 266, 20085.
12. The structure of BMS-183507: (equation presented)
13. A lipophilic moiety binding at the proximal pocket region enhances the potency of retro-binding thrombin inhibitors. Results to be published elsewhere.
14. (a) Sundberg, R. J.; Russel H. F. J. Org. Chem. 1973, 38, 3324.
15. (b) Kano, S.; Sugino, E.; Shibuya, S.; Hibino, S J. Org. Chem. 1981, 46, 2979.
16. Based on the SAR for the retro-binding peptide series, introduction of the fluorine atom was expected to enhance activity. These results will be published elsewhere.
17. Compound 13 was derived from cyclohexanone following the synthetic scheme outlined in Figure 2.
18. Cheng, Y. C.; Prusoff, W. H. Biochem. Pharm. 1973, 22, 3099.
19. SYBYL Molecular Modeling System, Versions 5 and 6, TRIPOS Assoc., St. Louis, MO, U.S.A.
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21. Blaney, J. M.; Crippen, G. M.; Dearing, A.; Dixson, J. S. DGEOM, Quantum Chemistry Program Exchange, Indiana University.
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