title: Potent and selective inhibitors of human immunodeficiency virus protease structurally related to L-694,746.
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.
authors.affiliation: Dipartimento di Scienze Chimiche, Università di Camerino, Italy. grima@camserv.unicam.it
authors.forename: P
authors.initials: P
authors.lastname: Franchetti
authors.forename: P
authors.initials: P
authors.lastname: Perlini
authors.forename: G
authors.initials: G
authors.lastname: Abu Sheikha
authors.forename: L
authors.initials: L
authors.lastname: Cappellacci
authors.forename: M
authors.initials: M
authors.lastname: Grifantini
authors.forename: A G
authors.initials: AG
authors.lastname: Loi
authors.forename: A
authors.initials: A
authors.lastname: De Montis
authors.forename: A
authors.initials: A
authors.lastname: Pani
authors.forename: M E
authors.initials: ME
authors.lastname: Marongiu
authors.forename: P
authors.initials: P
authors.lastname: La Colla
mesh_terms: D000577:Amides / Q000138:chemical synthesis; D019380:Anti-HIV Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D000998:Antiviral Agents / Q000138:chemical synthesis / Q000494:pharmacology; D002460:Cell Line; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D017320:HIV Protease Inhibitors / Q000138:chemical synthesis*; D006801:Humans; D015394:Molecular Structure; D009025:Morpholines / Q000494:pharmacology; D010455:Peptides / Q000494:pharmacology*
chemical_list: D000577:Amides; D019380:Anti-HIV Agents; D000998:Antiviral Agents; D004791:Enzyme Inhibitors; D017320:HIV Protease Inhibitors; D009025:Morpholines; D010455:Peptides; C072111:L 689502; C072112:L 694746