Solid phase synthesis of hydroxyethylamine peptide bond isosteres: Synthesis of the potent HIV-1 protease inhibitor JG365

✍ Scribed by Paul F. Alewood; Ross I. Brinkworth; Robert J. Dancer; Bronwyn Garnham; Alun Jones; Stephen B.H. Kent

• Publisher: Elsevier Science
• Year: 1992
• Tongue: French
• Weight: 274 KB
• Volume: 33
• Category: Article
• ISSN: 0040-4039
• DOI: 10.1016/s0040-4039(00)91592-2

✦ Synopsis

A protocol has been kvelopedjiu rht generation qf hylroxyehyhnine peptide bond isosmes in a poipcr- sqprted synthesis. This has been used to produce the potent HlV-I Protease inhibitor JG345 rqidiy and in good yield.

Protease inhibitors have outstanding potential as therapeutic agentst. Recently it has been shown that Human Immunodeficiency Virus-1 Pmtease (HIV-1 PR) is requited for infectivity of the AIDS virus2 and that inhibitors of HIV-1 PR are active against the virus in virrd. Efficient HIV-l protease inhibitors thus have the potential to be active anti -HIV-1 drugs. Most efforts in designing HIV-I PR inhibitors have centred on the production of proteolytically stable, isosteric peptide analogues. An early example involved the replacement of the P1 and P{ residues (1) with an isosteric dipcptidc unit where the carbonyl of the scissile amide bond was replaced with a methylene unit (2). Such isosteres. although simple, have been found to be effective protease inhibitor& They may be assembled directly on resins and as such allow for the rapid variation of PI, P2, PJ, PI', Pz', P3'.