Isophthalic acid derivatives: amino acid surrogates for the inhibition of HIV-1 protease

• Published in: Bioorganic & medicinal chemistry letters Vol. 5; no. 7; pp. 721 - 726
• Main Authors: Kaldor, Stephen W., Dressman, Bruce A., Hammond, Marlys, Appelt, Krzysztof, Burgess, Jeffrey A., Lubbehusen, Penny P., Muesing, Mark A., Hatch, Steven D., Wiskerchen, Mary Ann, Baxter, Angela J.
• Format: Journal Article
• Language: English
• Published: Elsevier Ltd 06.04.1995
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/0960-894X(95)00102-Y

Using the X-ray crystal structure of the inhibitor 1 complexed to HIV-1 protease, a new series of HIV-1 protease inhibitors was developed incorporating substituted isophthalic acid derivatives as amino acid surrogates. Through iterative structure-based design, the lead compound 2 was optimized to produce a variety of non-peptide HIV-1 protease inhibitors with significant antiviral activity. In contrast to 1, several members of this series exhibit significant oral absorption in animals. Using structure-based design, a new series of orally absorbed, non-peptide HIV-1 protease inhibitors has been discovered incorporating substituted isophthalic acid derivatives as amino acid replacements.