New, potent P1/P2-morpholinone-based HIV-protease inhibitors

We have developed efficient synthesis of morpholinone-based cyclic mimetics of the P1/P2 portion of the HIV-1 protease inhibitor Amprenavir. This effort led to discovery of allyl- and spiro-cyclopropyl—P2-substituted inhibitors 17 and 31, both 500 times more potent than the parent inhibitor 1. These results support morpholinones as novel mimetics of the P1/P2 portion of Amprenavir and potentially of other HIV-protease inhibitors, and thus provide a novel medicinal chemistry template for optimization toward more potent and drug-like inhibitors.

Graphical abstractMorpholinone-based P1/P2 derivatives have been discovered to provide a new and promising scaffold toward potent mimetics of the HIV-1 protease inhibitor Amprenavir. In particular, allyl- and spiro-cyclopropyl—P2-substituted inhibitors 17 and 31 were found 500× more potent than the parent inhibitor 1.Figure optionsDownload full-size imageDownload as PowerPoint slide