AIDSWEEKLY Plus; Monday, June 30, 2003
Staff Medical Writers

"The design, synthesis, and biological evaluation of a series of HIV-1 protease inhibitors [(-)-6, (-)-7, (-)-23, (+)-24] based upon the 3,5,5-trisubstituted pyrrolin-4-one scaffold" was reported by researchers in the United States.

"Use of a monopyrrolinone scaffold leads to inhibitors with improved cellular transport properties relative to the earlier inhibitors based on bispyrrolinones and their peptide counterparts," explained A.B. Smith and coauthors at the University of Pennsylvania.

"The most potent inhibitor (-)-7 displayed 13% oral bioavailability in dogs," they wrote in the Journal of Medicinal Chemistry. "X-ray structure analysis of the monopyrrolinone compounds cocrystallized with the wild-type HIV-1 protease provided valuable information on the interactions between the inhibitors and the HIV-1 enzyme."

"In each case, the inhibitors assumed similar orientations for the P2'-P1 substituents, along with an unexpected hydrogen bond of the pyrrolinone NH with Asp225," study data showed. "Interactions with the S2 pocket, however, were not optimal, as illustrated by the inclusion of a water molecule in two of the three inhibitor-enzyme complexes."

"Efforts to increase affinity by displacing the water molecule with second and third generation inhibitors did not prove successful. Lack of success with this venture is a testament to the difficulty of accurately predicting the many variables that influence and build binding affinity," according to the report. "Comparison of the inhibitor positions in three complexes with that of indinavir revealed displacements of the protease backbones in the enzyme flap region, accompanied by variations in hydrogen bonding to accommodate the monopyrrolinone ring."

"The binding orientation of the pyrrolinone-based inhibitors may explain their sustained efficacy against mutant strains of the HIV-1 protease enzyme as compared to indinavir," the researchers concluded.

Smith and colleagues published their study in the Journal of Medicinal Chemistry (Design, synthesis, and biological evaluation of monopyrrolinone-based HIV-1 protease inhibitors. J Med Chem. 2003 May 8;46(10):1831-44.

For additional information, contact A.B. Smith, University of Pennsylvania, Department of Chemistry, 231 S. 34th St., Philadelphia, PA 19104, USA.

The publisher's contact information for the Journal of Medicinal Chemistry is: American Chemical Society, 1155 16th St., NW, Washington, DC 20036, USA.

The information in this article comes under the major subject areas of AIDS and HIV and Drug Development.

This article was prepared by AIDS Weekly editors from staff and other reports.

Reference

Smith AB 3rd, Cantin LD, Pasternak A, et al., "Design, synthesis, and biological evaluation of monopyrrolinone-based HIV-1 protease inhibitors", J Med Chem. 2003 May 8;46(10):1831-44.

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