Dibasic benzo[b]thiophene derivatives as a novel class of active site directed thrombin inhibitors. 2. Exploring interactions at the proximal (S2) binding site

Bioorganic and Medicinal Chemistry Letters

Volumn 8, Issue 18, 1998, Pages 2527-2532

  Sall, Daniel J ^a   Briggs, Stephen L ^a   Chirgadze, Nickolay Y ^a   Clawson, David K ^a   Gifford Moore, Donetta S ^a   Klimkowski, Valentine J ^a   McCowan, Jefferson R ^a   Smith, Gerald F ^a   Wikel, James H ^a  

^a ELI LILLY AND COMPANY   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

BENZOTHIOPHENE DERIVATIVE; BROMIDE; METHANE; NITRIC OXIDE; THROMBIN INHIBITOR;

ARTICLE; BINDING SITE; CRYSTALLOGRAPHY; DEMETHYLATION; ENZYME ACTIVE SITE; HYDROPHILICITY; HYDROPHOBICITY; INHIBITION KINETICS; MOLECULAR MODEL; OXYGENATION; STRUCTURE ACTIVITY RELATION; THROMBOGENESIS;

BINDING SITES; CRYSTALLOGRAPHY, X-RAY; MODELS, CHEMICAL; MODELS, MOLECULAR; SERINE PROTEINASE INHIBITORS; STRUCTURE-ACTIVITY RELATIONSHIP; THIOPHENES; THROMBIN;

EID: 0032558508     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0960-894X(98)00447-8     Document Type: Article

References (19)

1. 1. Preliminary accounts of this work have been presented: Sall, D. J.; Bastian, J. A.; Denney, M.L.; Gifford-Moore, D.S.; Harper, R. W.; Kohn, T. J.; Lin, H-S; Rampersaud, A. A.; Smith, G. F.; Takeuchi K.; Zhang M. Abstract of Papers, 214th National Meeting of the American Chemical Society, Las Vegas, NV; American Chemical Society: Washington, DC, 1997.
2. 2. (a) Machovich, R. In The Thrombin; Machovich, R., Ed.; CRC Press, Inc: Boca Rotan, FL, 1984; Vol. 1, pp 1-22.
3. (b) Hirsh. J.; Salzman, E. W.; Marder, V. J.; Colman, R. W. In Hemostasis and Thrombosis: Basic Principles and Clinical Practice, 2nd ed.; Colman, R.W.; Hirsh, J.; Marder, V. J.; Salzman, E. W., Eds.; J. B. Lippincott Co.: Philadelphia, 1987; pp 1063-1072.
4. (c) Hirsh, J.; Salzman, E. Ibid. pp 1199-1207.
5. d) Barnett, H. J. M. Ibid. pp 1301-1315.
6. 3. For recent reviews on approaches to the design of active-site directed thrombin inhibitors see (a) Edmunds, J. J.; Rapundalo, S.T.; Ann. Rep. Med. Chem. 1996, 31, 51-60.
7. (b) Scarborough, R. M. Ann. Rep. Med. Chem. 1995, 30, 71-80.
8. (c) Wiley, M. R.; Fisher, M. J. Exp. Opin. Ther. Patents 1997, 7, 1265-1282.
9. 4. Sall, D. J.; Bastian, J. A.; Briggs, S. L.; Buben, J. A.; Chirgadze, N. Y.; Clawson, D. K.; Denney, M. L.; Giera, D. D.; Gifford-Moore, D. S.; Harper, R. W.; Hauser, K. L.; Klimkowski, V. J.; Kohn, T. J.; Lin, H-S.; McCowan, J. R.; Palkowitz, A. D.; Smith, G. F.; Takeuchi, K.; Thrasher, K. J.; Tinsley, J. M.; Utterback, B. G.; Van, S-CB.; Zhang, M. J. Med. Chem., 1997, 40, 3489-3493.
10. 5. A manuscript describing the X-ray crystallographic studies conducted with this series of thrombin inhibitors is in preparation.
11. m, and π, is contained in Martin, YC. Quantitative Drug Design: A Critical Introduction. New York: Marcel Dekker, Inc., 1978: 11-31.
12. m and π were taken from Hansch, C.; Leo, A. Substituent Constants for Correlation Analysis in Chemistry and Biology. New York: Wiley, 1979.
13. 1H NMR, MS, and IR. The experimentally determined elemental percentages of C, H and N were within 0.4 % of theoretical values.
14. 9. Bastian, J. A.; Chirgadze, N. Y.; Denney, M. L.; Foglesong, R. J.; Harper, R. W.; Johnson, M. G.; Klimkowski, V. J.; Kohn, T. J.; Lin, H-S.; Lynch, M. P.; McCowan, J. R.; Palkowitz, A. D.; Richett, M. E.; Sall, D. J.; Smith, G. F.; Takeuchi, K.; Tinsley, J. M.; Zhang, M. WO 97/25033, 1997.
15. 10. Stille, J. K. Angew. Chem. Int. Ed. Engl., 1986, 25, 508-524.
16. ass) which were derived from inhibition kinetics as previously described Smith, G. F.; Gifford-Moore, D.; Craft, T. J.; Chirgadze, N.; Ruterbories, K. J.; Lindstrom, T. D.; Satterwhite, J. H. Efegatran: A New Cardiovascular Anticoagulant. In: Pifarre, R, editor. New Anticoagulants for the Cardiovascular Patient. Philadelphia: Hanley & Belfus, Inc., 1997:265-300.
17. 4.5 was used as the starting point for all molecular modeling, which was performed using QUANTA/CHARMm (versions 96 and 23.2 respectively, Molecular Simulations Inc., San Diego, CA 92121). Each analog was built from the X-ray structure of 1b, as extracted from the experimental complex. Both amine nitrogens were protonated, and the initially assigned charges were smoothed over all carbon and hydrogen atoms for a net +2 charge. All hydrogens were added and refined for the protein and crystallographic waters by the HBUILD procedure. The ligand binding region was solvated with a 20 Å sphere of TIPS3P water, centered at a point central to the active site. Each analog was processed by reinserting into the active site, deleting all waters having a oxygen within 2.0 Å of a ligand atom, and the complex energy was minimized (ABNR) to convergence (gradient tolerance 0.01 kcal/mole-Å). With respect to the active site center, the region minimized included all protein residues within 14 Å, all waters within 20 Å, and the considered analog. The nonbonded interactions were treated using a 13 Å cutoff and smoothed to 0.0 by a force switch function for electrostatics (applied between 8 Å to 12 Å), and a shift function for the van der Waals.
18. 13. For the model system para-methoxy toluene, respectively the meta-methyl and the meta-trifluromethyl analogs were built and processed with SPARTAN 5.0.1 (Wavefunction Inc., Irvine, CA 92612). For each, the geometry was optimized using the AM1 Hamiltoman. Then for each, electrostatic potential fit atomic charges were calculated with the 3-21G(*) basis set.
19. 14. The C-2″ bromo derivative 2p was prepared by essentially the same route as the C-3″ bromide 2a (Scheme 1) except that 2-bromo-4-methoxybenzoyl chloride was employed as the acylating reagent in the first step.