The DOI matches its Crossref record; 1 of the 1 references it cites were found in a registry or an index.
Discovery of Ritonavir, a Potent Inhibitor of HIV Protease with High Oral Bioavailability and Clinical Efficacy
Open accessAbstract
The structure-activity studies leading to the potent and clinically efficacious HIV protease inhibitor ritonavir are described. Beginning with the moderately potent and orally bioavailable inhibitor A-80987, systematic investigation of peripheral (P3 and P2') heterocyclic groups designed to decrease the rate of hepatic metabolism provided analogues with improved pharmacokinetic properties after oral dosing in rats. Replacement of pyridyl groups with thiazoles provided increased chemical stability toward oxidation while maintaining sufficient aqueous solubility for oral absorption. Optimization of hydrophobic interactions with the HIV protease active site produced ritonavir, with excellent in vitro potency (EC50 = 0.02 microM) and high and sustained plasma concentrations after oral administration in four species. Details of the discovery and preclinical development of ritonavir are described.
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Göttlinger, H. G., Sodroski, J. G., & Haseltine, W. A. (1989) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.86.15.5781 · Cited by 841
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Metadata
- Authors
- Kempf, D. J., Sham, H. L., Marsh, K. C., Flentge, C. A., Betebenner, D., Green, B. E., McDonald, E., Vasavanonda, S., Saldivar, A., Wideburg, N. E., Kati, W. M., Ruiz, L., Zhao, C., Fino, L., Patterson, J., Molla, A., Plattner, J. J., & Norbeck, D. W.
- Venue
- Journal of Medicinal Chemistry
- Publisher
- American Chemical Society (ACS)
- Published
- 1998-01-22
- Volume
- 41
- Issue
- 4
- Pages
- 602-617
- ISSN
- 0022-2623 (ISSN-L)
- 1520-4804
- OpenAlex
- W2162324851
- Cited by
- 205
- References
- 1
- FWCI
- 7.41
- Type
- journal article
- Language
- en
- Open access
- green
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- Kempf, D. J., Sham, H. L., Marsh, K. C., Flentge, C. A., Betebenner, D., Green, B. E., McDonald, E., Vasavanonda, S., Saldivar, A., Wideburg, N. E., Kati, W. M., Ruiz, L., Zhao, C., Fino, L., Patterson, J., Molla, A., Plattner, J. J., & Norbeck, D. W. (1998). Discovery of Ritonavir, a Potent Inhibitor of HIV Protease with High Oral Bioavailability and Clinical Efficacy. Journal of Medicinal Chemistry. https://doi.org/10.1021/jm970636%2B
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Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).
Semantic Scholar’s data is described in: Kinney, R., et al. (2023). The Semantic Scholar Open Data Platform. arXiv:2301.10140.
