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Potent and selective inhibitors of human immunodeficiency virus protease structurally related to L-694,746

Authors :
G. Abu Sheikha
Palmarisa Franchetti
Loredana Cappellacci
Ag Loi
P Perlini
Mario Grifantini
P. La Colla
Alessandra Pani
A. De Montis
Me Marongiu
Source :
Scopus-Elsevier
Publication Year :
1998
Publisher :
International Medical Press:2-4 Idol Lane, London EC3R 5DD United Kingdom:011 44 207 3980700, EMAIL: imp@intmedpress.com, INTERNET: http://www.intmedpress.com, Fax: 011 44 207 3980701, 1998.

Abstract

A series of human immunodeficiency virus (HIV) protease inhibitors, which are analogues of N-[2( R)-hydroxy-1( S)-indanyl]-5( S)-[( tert-butyloxycarbonyl)amino]-4( S)-hydroxy-6-phenyl-2-( R)-[[4-(carboxymethoxy)phenyl]methyl]hexanamide (L-694,746), a metabolite of the anti-HIV agent L-689,502, were synthesized. In these compounds, the acetic group linked to the para position of the P1′ phenyl in the reference inhibitor was replaced either by the bioisosteric phosphonomethoxy group and its diisopropyl/dibenzyl derivatives, or the 1H-tetrazol-5-yl-methoxy group and its 1-benzyl derivative. In enzyme assays, phosphonomethoxy and tetrazolmethoxy analogues proved to be potent inhibitors of the HIV-1 protease, with IC50 values as low as 0.04 nM. When tested for anti-HIV-1 activity in cell-based assays, most of the new derivatives proved active, with benzyl derivatives being more active than their highly polar, unsubstituted counterparts. The dibenzylphosphonomethoxy analogue was the most active compound, with an EC50 value of 10 nM and a selectivity index of 20 000. When compounds were examined for their capability to reduce p24 levels in both acutely and chronically infected MT-4 and H9/IIIB cells, all of them were found to be active at concentrations close to those capable of preventing HIV-1-induced cytopathic effect.

Details

Language :
English
Database :
OpenAIRE
Journal :
Scopus-Elsevier
Accession number :
edsair.doi.dedup.....ea9bbefdc08b50ef99b4f0f8e90e67bd