The design of potent, selective, non-covalent, peptide thrombin inhibitors utilizing imidazole as a S1 binding element

Bioorganic and Medicinal Chemistry Letters

Volumn 9, Issue 18, 1999, Pages 2767-2772

  Wiley, Michael R ^a   Weir, Leonard C ^a   Briggs, Steven L ^a   Chirgadze, Nickolay Y ^a   Clawson, David ^a   Gifford Moore, Donetta S ^a   Schacht, Aaron L ^a   Smith, Gerald F ^a   Vasudevan, Vasu ^a   Zornes, Larry L ^a   Klimkowski, Valentine J ^a  

^a ELI LILLY AND COMPANY   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

FUNCTIONAL GROUP; IMIDAZOLE DERIVATIVE; THROMBIN INHIBITOR;

ANTICOAGULATION; ARTICLE; BINDING AFFINITY; DRUG DESIGN; MOLECULAR MODEL; STEREOCHEMISTRY; STRUCTURE ACTIVITY RELATION; STRUCTURE ANALYSIS;

ANTITHROMBINS; BINDING SITES; CRYSTALLOGRAPHY, X-RAY; DRUG DESIGN; HUMANS; IMIDAZOLES; MODELS, MOLECULAR; PEPTIDES;

EID: 0033588995     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0960-894X(99)00459-X     Document Type: Article

References (14)

1. 1. (a) Vacca, J. P. Ann. Rep. Med. Chem. 1998, 33, 81.
2. (b) Sanderson, P. E. J.; Naylor-Olsen, A. M. Cur. Med. Chem. 1998, 5, 289.
3. (c) Wiley, M. R.; Fisher, M. J. Exp. Op. Ther. Patents 1997, 7, 1265.
4. 2. Wiley, M. R.; Chirgadze, N. Y.; Clawson, D. K.; Craft, T. J.; Gifford-Moore, D. S.; Jones, N. D.; Olkowski, J. L.; Schacht, A. L.; Weir, L. C.; Smith G. F. Bioorg. Med. Chem. Lett. 1995, 5, 2835.
5. 3. Wiley M. R.; Chirgadze, N. Y.; Clawson, D. K.; Craft, T. J.; Gifford-Moore, D. S.; Jones, N. D.; Olkowski, J. L.; Weir, L. C.; Smith G. F. Bioorg. Med. Chem. Lett. 1996, 6, 2387.
6. 2 The protein system was prepared by removing the inhibitor, adding all hydrogens to the protein and resolved water molecules, and then optimizing the hydrogen positions with successive applications of the HBUTLD procedure. Water molecules were then removed. Optimum positions for an imidazolium ion (+1 total charge) were investigated by energy minimization in the environment of the rigid protein structure. The D-Phe-Pro-NH scaffold was constructed by editing the original ligand X-ray structure. This scaffold was reinserted into the active site and geometric measurements made to determine the range of tethers to consider. Analogs were each processed, first by energy minimizing the introduced linkage and the imidazole group while the inhibitor scaffold portion and the protein were fixed in space. This was further processed by reinserting the crystallographic waters and then solvating the active site with a 20Å water sphere. For the final systems the total ligand, all protein residues having an atom within 14Å, and all waters within 20Å (of the active site center) were then energy minimized.
7. 5. For other reports on the use of imidazole in S1 binding elements, see: (a) Dominguez, C.; Carini, D. J.; Weber, P. C.; Knabb, R. M.; Alexander R. S.; Kettner, C. A.; Wexler R. R Bioorg. Med. Chem. Lett. 1997, 7, 79.
8. (b) Issacs, R. C. A.; Newton, C. L.; Solinsky, M. G.; Naylor-Olsen, A. M. 217th National ACS Meeting, Anaheim, CA, March 1999, Abstract MEDI-005.
9. 6. Sellier, C.; Buschauer, A.; Elz, S.; Schunack, W. Liebigs Ann. Chem. 1992, 317.
10. 5 the target molecules were prepared using D-Cha-Pro since this modification was known to produce some increase in thrombin affinity and yet maintain a similar overall binding orientation (Schacht, A.L.; Smith G. F.; Wiley, M. R. U. S. Patent 5,705,487; Chem. Abstr. 1998, 128, 128286). For experimental details of the synthesis of compounds 9-17, see Klimkowski, V. J.; Wiley, M. R. US Patent 5,811,402; Chem. Abstr. 1998, 729, 265470.
11. 8. Titrations were performed according to the method of Slater, B.; McCormack, A.; Avdeef, A.; Comer, J. E. A. J. Pharm. Sci. 1994, 83, 1280.
12. 9. Teger-Nilsson, A.; Bylund, R.; Gustafsson, D.; Gyzander E.; Eriksson, U. Thromb. Res. 1997, 85, 133.
13. 10. Chirgadze, N. Y.; Schacht, A. L.; Smith G. F.; Wiley, M. R. US Patent 5,599,793; Chem. Abstr. 1995, 723, 306600f.
14. free of 23.3% was calculated, using a random selection of approximately 5% of the data not involved in the crystallographic refinement. The root mean square deviation from ideal bond lengths was 0.010 Å, that from ideal angles 1.5°. Model inspection and correction between cycles of the refinement and crystallographic refinement itself was performed within the QUANTA97 and X-PLOR98 program suites (Molecular Simulations Inc., San Diego, CA).