Pyrrolobenzoxazepinone Derivatives as Non-Nucleoside HIV-1 RT Inhibitors: Further Structure-Activity Relationship Studies and Identification of More Potent Broad-Spectrum HIV-1 RT Inhibitors with Anti

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• 作者：Giuseppe Campiani ; Elena Morelli ; Monica Fabbrini ; Vito Nacci ; Giovanni Greco ; Ettore Novellino ; Anna Ramunno ; Giovanni Maga ; Silvio Spadari ; Giuseppe Caliendo ; Alberto Bergamini ; Emanuela Faggioli ; I
• 刊名：Journal of Medicinal Chemistry
• 出版年：1999
• 出版时间：October 21, 1999
• 年：1999
• 卷：42
• 期：21
• 页码：4462 - 4470
• 全文大小：239K
• 年卷期：v.42,no.21(October 21, 1999)
• ISSN：1520-4804

文摘

Pyrrolobenzoxazepinone (PBO) derivatives represent a new class of human immunodeficiencyvirus type 1 (HIV-1) non-nucleoside reverse transcriptase (RT) inhibitors (NNRTs) whoseprototype is (±)-6-ethyl-6-phenylpyrrolo[2,1-d][1,5]benzoxazepin-7(6H)-one (6). Docking studiesbased on the three-dimensional structure of RT prompted the synthesis and biological evaluationof novel derivatives and analogues of 6 featuring a meta-substituted phenyl or a 2-thienylring at C-6 and a pyridine system in place of the fused-benzene ring to yield pyrrolopyridooxazepinones (PPOs). Compared with the lead 6 and nevirapine, several of the synthesizedcompounds (PBOs 13a-d and PPOs 13i-k) displayed higher inhibitory activity against wild-type RT and clinically relevant mutant RTs containing the single amino acid substitutionsL100I, K103N, V106A, Y181I, and Y188L. The most potent inhibitors were further evaluatedfor in vitro antiviral activity on lymphocytes and monocyte-macrophages, for cytotoxicity on apanel of cell lines, and for potential synergistic antiviral activity with AZT. Pharmacokineticstudies performed on 13b, 13c, and 13i showed that these compounds achieve high concentrations in the brain. The results of the biological and pharmacokinetic experiments suggest apotential clinical utility of analogues such as 13b-d, 13i, and 13j, in combination withnucleoside RT inhibitors, against strains of HIV-1 bearing those mutations that confer resistanceto known NNRTI.