Structure-activity relationship of orally potent tripeptide-based HIV protease inhibitors containing hydroxymethylcarbonyl isostere

We designed and synthesized a new class of peptidomimetic human immunodefic iency virus protease inhibitors containing a unique unnatural amino acid, a llophenylnorstatine [Apns; (2S,3S)-3-amino-2-hydroxy-4-phenylbutyric acid], with a hydroxymethylcarbonyl isostere as the active moiety. From a structu re-activity relationship study of HIV-1 protease inhibition. enzyme selecti vity for other aspartyl proteases, the antiviral activity and pharmacokinet ics in rats, 24c (KNI-227) and 24d (KNI-272, our first clinical candidate) were found to be selective and orally potent HIV protease inhibitors. Moreo ver, an improvement of the pharmacokinetic features of KNI-272 provided two long-lasting and highly bioavailable compounds (24g: JE-2178, 24h: JE-2179 ).