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De Novo Design and Discovery of Cyclic HIV Protease Inhibitors Capable of Displacing the Active-Site Structural Water Molecule

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Integration of Pharmaceutical Discovery and Development

Part of the book series: Pharmaceutical Biotechnology ((PBIO,volume 11))

Conclusion

Combining the Caco-2 cell assay, dog pharmacokinetic assessment on selected compounds, antiviral testing against wild-type and mutant variants, and antiviral testing in the presence of human plasma proteins, we can define the overall quality of a given compound. We can then select compounds for further preclinical evaluation.

Using this refined strategy we have been able to identify unsymmetrical analogues that have good potency, resistance profiles, and physicochemical properties, while maintaining excellent oral pharmacokinetics. The true test of our strategy and our assays’ predictive power lies in phase I clinical trials.

We believe that many other opportunities are available (in the area of cyclic HIV-PR inhibitors capable of displacing the structural water) to find structurally different drug candidates with superior potency, mutation profiles, and pharmacokinetics. This area includes cyclic sulfamides, cyclic thioureas, cyclic sulfones, and azacyclic ureas. Extensive analogue SAR studies in these areas await further work.

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  1. DuPont Merck Pharmaceutical Company, Experimental Station, Wilmington, Delaware, 19880-0500

    George V. De Lucca, Prabhakar K. Jadhav, Robert E. Waltermire, Bruce J. Aungst, Susan Erickson-Viitanen & Patrick Y. S. Lam

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  1. The University of Kansas, Lawrence, Kansas

    Ronald T. Borchardt

  2. Merck Research Laboratories, West Point, Pennsylvania

    Roger M. Freidinger

  3. ARIAD Pharmaceuticals, Inc., Cambridge, Massachusetts

    Tomi K. Sawyer

  4. Smith Kline Beecham, Collegeville, Pennsylvania

    Philip L. Smith

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De Lucca, G.V., Jadhav, P.K., Waltermire, R.E., Aungst, B.J., Erickson-Viitanen, S., Lam, P.Y.S. (2002). De Novo Design and Discovery of Cyclic HIV Protease Inhibitors Capable of Displacing the Active-Site Structural Water Molecule. In: Borchardt, R.T., Freidinger, R.M., Sawyer, T.K., Smith, P.L. (eds) Integration of Pharmaceutical Discovery and Development. Pharmaceutical Biotechnology, vol 11. Springer, Boston, MA. https://doi.org/10.1007/0-306-47384-4_12

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