Lead development: Validation and application of high throughput screening for determination of pharmacokinetic parameters for enzyme inhibitors

Bioorganic and Medicinal Chemistry

Volumn 4, Issue 5, 1996, Pages 639-643

  Singh, Jasbir ^a,b   Soloweij, Jim ^a   Allen, Martin ^a   Killar, Loran ^a   Ator, Mark ^a  

^a Sterling Winthrop Pharmaceutical R ^*  (United States)

^b Nycomed Inc   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ENZYME INHIBITOR; PROTEINASE INHIBITOR;

BIOASSAY; BLOOD ANALYSIS; CONFERENCE PAPER; DRUG DETERMINATION; QUANTITATIVE STRUCTURE ACTIVITY RELATION; ROBOTICS;

EID: 0029996821     PISSN: 09680896     EISSN: None     Source Type: Journal    
DOI: 10.1016/0968-0896(96)00057-0     Document Type: Conference Paper

References (21)

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3. Hobbs DeWitt, S.; Kiely, J. S.; Stankovic, C. J.; Schroeder, M. C.; Reynolds Cody, D. M.; Pavia, M. R. Proc. Natl. Acad. Sci. U.S.A. 1993, 90, 6909.
4. (a) Vacca, J. P.; Dorsey, B. D.; Schleif, W. A.; Levin, R. B..; McDaniel, S. L.; Darke, P. L.; Zugay, J.; Quintro, J. C.; Blahy, O. M.; Royh, E.; Sardana, V. V.; Schlahach, A. J.; Graham, P. I.; Condra, J. H.; Gotlib, L.; Holloway, M. K.; Lin, J.; Chen, I. W.; Vastag, K.; Ostovic, D.; Anderson, P. S.; Emini, E. A.; Huff, J. R. Proc. Natl. Acad. Sci. U.S.A. 1994, 91, 4096. (b) Rosenberg, S. H.; Spina, K. P.; Condon, S. L.; Polakowski, J.; Yao, Z.; Kovar, P.; Stein, H. H.; Cohen, J.; Barlow, J. L.; Klinghofer, V.; Egan, D. A.; Tricarico, K. A.; Perun, T. J.; Baker, W. R.; Kleinert, H. D. J. Med. Chem. 1993, 36, 460. Rosenberg, S. H.; Spina, K. P.; Wood, K. W.; Polakowski, J.; Martin, D. L.; Yao, Z.; Stein, H. H.; Cohen, J.; Barlow, J. L.; Egan, D. A.; Tricarico, K. A.; Baker, W. R.; Kleinert, H. D. J. Med. Chem. 1993, 36, 449.
5. (a) Vacca, J. P.; Dorsey, B. D.; Schleif, W. A.; Levin, R. B..; McDaniel, S. L.; Darke, P. L.; Zugay, J.; Quintro, J. C.; Blahy, O. M.; Royh, E.; Sardana, V. V.; Schlahach, A. J.; Graham, P. I.; Condra, J. H.; Gotlib, L.; Holloway, M. K.; Lin, J.; Chen, I. W.; Vastag, K.; Ostovic, D.; Anderson, P. S.; Emini, E. A.; Huff, J. R. Proc. Natl. Acad. Sci. U.S.A. 1994, 91, 4096. (b) Rosenberg, S. H.; Spina, K. P.; Condon, S. L.; Polakowski, J.; Yao, Z.; Kovar, P.; Stein, H. H.; Cohen, J.; Barlow, J. L.; Klinghofer, V.; Egan, D. A.; Tricarico, K. A.; Perun, T. J.; Baker, W. R.; Kleinert, H. D. J. Med. Chem. 1993, 36, 460. Rosenberg, S. H.; Spina, K. P.; Wood, K. W.; Polakowski, J.; Martin, D. L.; Yao, Z.; Stein, H. H.; Cohen, J.; Barlow, J. L.; Egan, D. A.; Tricarico, K. A.; Baker, W. R.; Kleinert, H. D. J. Med. Chem. 1993, 36, 449.
6. (a) Vacca, J. P.; Dorsey, B. D.; Schleif, W. A.; Levin, R. B..; McDaniel, S. L.; Darke, P. L.; Zugay, J.; Quintro, J. C.; Blahy, O. M.; Royh, E.; Sardana, V. V.; Schlahach, A. J.; Graham, P. I.; Condra, J. H.; Gotlib, L.; Holloway, M. K.; Lin, J.; Chen, I. W.; Vastag, K.; Ostovic, D.; Anderson, P. S.; Emini, E. A.; Huff, J. R. Proc. Natl. Acad. Sci. U.S.A. 1994, 91, 4096. (b) Rosenberg, S. H.; Spina, K. P.; Condon, S. L.; Polakowski, J.; Yao, Z.; Kovar, P.; Stein, H. H.; Cohen, J.; Barlow, J. L.; Klinghofer, V.; Egan, D. A.; Tricarico, K. A.; Perun, T. J.; Baker, W. R.; Kleinert, H. D. J. Med. Chem. 1993, 36, 460. Rosenberg, S. H.; Spina, K. P.; Wood, K. W.; Polakowski, J.; Martin, D. L.; Yao, Z.; Stein, H. H.; Cohen, J.; Barlow, J. L.; Egan, D. A.; Tricarico, K. A.; Baker, W. R.; Kleinert, H. D. J. Med. Chem. 1993, 36, 449.
7. We have routinely used a battery of in situ models for a number of protease inhibitor based projects. Development of elastase inhibitors is an example of the successful integration of this approach to drug discovery, see: Hlasta, D. J.; Subramanyam, C.; Bell, M. R.; Carbateas, P. M.; Court, J. J.; Desai, R. C.; Drozd, M. L.; Eickhoff, M. ; Ferguson, E. W.; Gordon, R. J.; Johnson, J. A.; Kumar, V.; Maycock, A. L.; Mueller, K. R.; Pagani, E. D.; Robinson, D. T.; Saindaine, M. T.; Silver, P. A.; Subramanyam, S.; Dunlap, R. P.; Frank, C. A.; Mura, A. J.; Rowlands, A. G. J. Med. Chem. 1995, 38, 739.
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9. Singh, J.; Allen, M. P.; Ator, M. A.; Gainor, J. A.; Whipple, D. A.; Solowiej, J. E.; Treasurywala, A. M.; Morgan, B. A.; Gordon, T. D.; Upson, D. A. J. Med. Chem. 1995, 38, 217.
10. (a) Kick. E.K; Ellman, J. A. J. Med. Chem. 1995, 38, 1427. (b) Wang, G. T.; Norman, S. L.; Wideburg, N.; Krafft, G. A.; Kempf, D. J. J. Med. Chem. 1995, 38, 2995.
11. (a) Kick. E.K; Ellman, J. A. J. Med. Chem. 1995, 38, 1427. (b) Wang, G. T.; Norman, S. L.; Wideburg, N.; Krafft, G. A.; Kempf, D. J. J. Med. Chem. 1995, 38, 2995.
12. One should be able to employ a variety of continuous soluble substrates (including fluorescence energy transfer substrates) as long as one could efficiently automate the given assay protocol for the determination of the inhibitor concentration in various biological fluids, analogous to the description provided here.
13. We have recently reported the pharmacokinetic parameter determinations for a series of compounds with variations at the terminal N-methyl amide portion of inhibitor 1, and all this work was performed with < 100 mg of each of these compounds.
14. We have recently identified a number of substrates which are processed selectively by human fibroblast stromelysin, and are not cleaved by mCl-t. This work will be reported elsewhere.
15. Details for the preparation of homogenous linker will be published elsewhere, Singh, J. et al.
16. Gainor, J. A.; Gordon, T. D.; Morgan, B. A. In Peptides, Proceedings of the 13th American Peptide Symposia, Hodges, R. S.; Smith J. A., Eds.; ESCOM: Leiden, 1994; pp 989-991.
17. (a) Singh, J.; Gainor, G. A.; Gordon, T. D.; Morgan, B. A.; Schneider, E.; Wahl, R. Poster presented at the Tenth American Peptide Symposium, Boston, MA, 1989. (b) Gowravaram, M. R.; Tomczuk, B. E.; Johnson, J. S.; Delecki, D.; Cook. E. R.; Ghose, A. K.; Mathiowetz, A. M.; Sprulino, J. C.; Rubin, B.; Smith, D. L.; Pulvino, T.; Whal., R. C. J. Med. Chem. 1995, 38, 2570.
18. (a) Singh, J.; Gainor, G. A.; Gordon, T. D.; Morgan, B. A.; Schneider, E.; Wahl, R. Poster presented at the Tenth American Peptide Symposium, Boston, MA, 1989. (b) Gowravaram, M. R.; Tomczuk, B. E.; Johnson, J. S.; Delecki, D.; Cook. E. R.; Ghose, A. K.; Mathiowetz, A. M.; Sprulino, J. C.; Rubin, B.; Smith, D. L.; Pulvino, T.; Whal., R. C. J. Med. Chem. 1995, 38, 2570.
19. Details of the modifications/customizations to the HP ORCA robot will be published elsewhere.
20. Since the plasma extract contains 75% methanol, the final concentration of methanol in the enzyme assays is 15%.
21. Brownell, J.; Earley W.; Kunec, E.; Morgan. B. A.; Olyslager, B.; Wahl, R. C.; Houck, D. R. Arch. Biochem. Biophys. 1995, 314, 120.