Conclusions
A program directed toward the discovery and development of novel and efficacious nonnucleoside HIV RT inhibitors involved a close collaboration between medicinal chemists and biologists and their colleagues in drug delivery, drug metabolism, and drug safety. An initial clinical candidate, PNU-87201E (atevirdine mesylate), helped pave the way for a far more potent and effective second-generation BHAP candidate, delavirdine mesylate (PNU-90152T). Emerging results from clinical trials suggest that delavirdine mesylate is a promising new agent for the treatment of AIDS.
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References
Bergren, M. S., Chao, R. S., Meulman, P. A., Sarver, R. W., Lyster, M A., Havens, J. L., and Hawley, M., 1996, Solid phases of delavirdine mesylate, J. Pharm. Sci. 85:834–841.
Chang, M., Sood, V. K., Kloosterman, D. A., Hauer, M. J., Gaerness, P. E., Sanders, P. E., and Vrbanac, J. J., 1997, Identification of the metabolites of the HIV-1 reverse transcriptase inhibitor delavirdine in monkeys, Drug Metab. Dispos. 25:828–839.
Chang, M., Sood, V. K., Wilson, G. J., Kloosterman, D. A., Sanders, P. E., Hauer, M. J., and Fagerness, P. E., 1997, Metabolism of the HIV-1 reverse transcriptase inhibitor delavirdin in rats, Drug Metab. Dispos. 25:228–242.
Chang, M., Sood, V. K., Wilson, G. J., Kloosterman, D. A., Sanders, P. E., Hauer, M. J., Zhang, W., and Granstetter, D. G., 1997, Metabolism of the HIV-1 reverse transcriptase inhibitor delavirdine in mice, Drug Metab. Dispos. 25:814–827.
Chong, K. T., Pagano, P. J., and Hinshaw, R. R., 1994, Bisheteroaryl piperazine reverse transcriptase inhibitor in combination with 3′-azido-3′-deoxythymidine or 2′,3-dideoxycytidine synergistically inhibits human immunodeficiency virus type I replication in vitro, Antimicrob. Agents Chemother. 38:288–293.
Davey, R. T., Chaitt, D. G., Reed, G. F., Freimuth, W. W., Herpin, B. R., Metcalf, J. A., Eastman, P. S., Falloon, J., Kovacs, J. A., Polis, M. A., Walker, R. E., Masur, H., Boyle, J., Coleman, S., Cox, S. R., Wathen, L., Daenzer, C. L., and Lane, H. C., 1996, Randomized, controlled phase I/II trial of combination therapy with delavirdine (U-90152S) and conventional nucleosides in human immunodeficiency virus type I-infected patients, Antimicrob. Agents Chemother. 40:1657–1664.
DeClercq, E., 1994, HIV resistance to reverse transcriptase inhibitors, Biochem. Pharmacol. 47:155–169.
Dueweke, T. J., Poppe, S. M., Romero, D. L., Swaney, S. M., So, A. G., Downey, K. M., Althaus, I. W., Reusser, F., Busso, M., Resnick, L., Mayers, D. L., Lane, J., Aristoff, P. A., Thomas, R. C., and Tarpley, W. G., 1993a, U-90152, a potent inhibitor of human immunodeficiency virus type I replication, Antimicrob. Agents Chemother. 37:1127–1131.
Dueweke, T. J., Pushkarskaya, T., Poppe, S. M., Swaney, S. M., Zhao, J. Q., Chen, I. S. Y., Stevenson, M., and Tarpley, W. G., 1993b, A mutation in reverse transcriptase in bis(heteroaryl)piperazine-resistant human immunodeficiency virus type I that confers sensitivity to other nonnucleoside inhibitors, Proc. Natl. Acad. Sci. USA 90:4713–4717.
Fischl, M. A., Richman, D. D., Grieco, M. H., Gottlieb, M. S., Volberding, P. A., Lasking, O. L., Lecdom, J. M., Groopman, J. E., Mildvan, D., Schooley, R. T, Jakson, G. G., Durack, D. T, King, D., and the AZT Collaborative Working Group, 1987, The efficacy of azidothymidine (AZT) in the treatment of patients with AIDS and AIDS-related complex. A double-blind, placebo-controlled trial, N. Engl. J. Med. 317:185–191.
Gottlieb, M. S., Schroff, R., Shanker, H. M., Weisman, J. D., Fan, P. T., Wolf, R. A., and Saxon, A., 1981, Pneumocystis carinii pneumonia and mucosal candidiasis in previously healthy homosexual men: Evidence of a new acquired cellular immunodeficiency, N. Eng. J. Med. 305:1425–1431.
Ho, D. D., Neumann, A. G., Perelson, A. S., Chen, W., Leonard, J. M., and Markowitz, M., 1995, Rapid turnover of plasma virions and CD4 lymphocytes in HIV-1 infection, Nature 373:123–126.
Mieke, A., Been-Tiktak, M., Vrehen, H. M., Schneider, M. M. E., van der Feltz, M., Branger, T, Ward, P., Cox, S. R., Harry, J. D., and Borleffs, J. C., 1995, Safety, tolerance, and pharmacokinetics of atevirdine mesylate (U-87201E) in asymptomatic human immunodeficiency virus-infected patients, Antimicrob. Agents Chemother. 39:602–607.
Quinn, T. C., 1996, Global burden of the HIV pandemic, Lancet 348:99–105.
Romero, D. L., Busso, M., Tan, C. K., Reusser, E, Palmer, J. R., Poppe, S. M., Aristoff, P. A., Downey, K. M., So, A. G., Resnick, L., and Tarpley, W. G., 1991, Nonnucleoside reverse transcriptase inhibitors that potently and specifically block human immunodeficiency virus type I replication, Proc. Natl. Acad. Sci. USA 88:8806–8810.
Romero, D. L., Morge, R. A., Genin, M. J., Biles, C., Busso, M., Resnick, L., Althaus, I. W., Reusser, F., Thomas, R. C., and Tarpley, W. G., 1993, Bis(heteroaryl)piperazine (BHAP) reverse transcriptase inhibitors: Structure-activity relationships of novel substituted indole analogues and the identification of l-[(5-methanesulfonamido-lH-indol-2-yl)carbonyl]-4-[3-[(l-methylethyl)-amino]pyridinyljpiperazine monomethanesulfonate (U-90152S), a second-generation clinical candidate, J. Med. Chem. 36:1505–1508.
Romero, D. L., Morge, R. M., Biles, C., Berrios-Pena, N., Max, P. D., Smith, H. W., Busso, M., Tan, C. K., Voorman, R. L., Reusser, F, Althaus, I. W., Downey, K., So, A. G., Resnick, L., Tarpley, W. G., and Aristoff, P. A., 1994, Discovery, synthesis, and bioactivity of bis(heteroaryl)piperazines. 1. A novel class of non-nucleoside HIV-1 reverse transcriptase inhibitors, J. Med. Chem. 37:999–1014.
Romero, D. L., Olmsted, R. A., Poel, T. J., Morge, R. A., Biles, C., Keiser, B. J., Kopta, L. A., Friis, J. M., Hosley, J. D., Stefanski, K. J., Wishka, D. G., Evans, D. B., Morris, J., Stehle, R. G., Sharma, S. K., Yagi, Y., Voorman, R. L., Adams, W. J., Tarpley, W. G., and Thomas, R. C., 1996, Targeting delavirdine/atevirdine resistant HIV-1: Identification of (alkylamino)piperidine-containing bis(heteroaryl)piperazines as broad spectrum HIV-1 reverse transcriptase inhibitors, J. Med. Chem. 39:3769–3789.
Staton, B. A., Johnson, M. G., Friis, J. M., and Adams, W. J., 1995, Simple, rapid and sensitive high-performance liquid chromatographic determination of delavirdine and its N-desisopropyl metabolite in human plasma, J. Chromatogr. B 668:99–106.
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Adams, W.J. et al. (2002). Discovery and Development of the BHAP Nonnucleoside Reverse Transcriptase Inhibitor Delavirdine Mesylate. 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_13
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