Orally Active CCR5 Antagonists as Anti-HIV-1 Agents: Synthesis and Biological Activity of 1-Benzothiepine 1,1-Dioxide and 1-Benzazepine Derivatives Containing a Tertiary Amine Moiety

Citations Over Time

Abstract

The search for orally active CCR5 antagonists was performed by chemical modification of the 1-benzothiepine 1,1-dioxide 3 and 1-benzazepine 4 lead compounds containing a tertiary amine moiety. Replacement of methyl group with a 2-(C(2-4) alkoxy)ethoxy group at the 4-position on the 7-phenyl group of the 1-benzothiepine ring resulted in both enhanced activity and significant improvement in the pharmacokinetic properties upon oral administration in rats. Introduction of C(2-4) alkyl, phenyl or (hetero)arylmethyl groups as the 1-substituent on the 1-benzazepine ring together with the 2-(butoxy)ethoxy group led to further increase of activity. Among the 1-benzazepine derivatives, the isobutyl (6i), benzyl (6o) or 1-methylpyrazol-4-ylmethyl (6s) compounds were found to exhibit highly potent inhibitory effects, equivalent to the injectable CCR5 antagonist 1, in the HIV-1 envelope-mediated membrane fusion assay. In particular, compound 6s showed the most potent CCR5 antagonistic activity (IC(50)=2.7 nM) and inhibitory effect (IC(50)=1.2 nM) on membrane fusion, together with good pharmacokinetic properties in rats. The synthesis of 1-benzothiepine 1,1-dioxide and 1-benzazepine derivatives and their biological activity are described.

Related Papers

• → 4-Amido-2-aryl-1,2,4-triazolo[4,3-a]quinoxalin-1-ones as New Potent and Selective Human A₃Adenosine Receptor Antagonists. Synthesis, Pharmacological Evaluation, and Ligand−Receptor Modeling Studies(2006)56 cited
• → Nitro and amino substitution within the A-ring of 5H-8,9-dimethoxy-5-(2-N,N-dimethylaminoethyl)dibenzo[c,h][1,6]naphthyridin-6-ones: influence on topoisomerase I-targeting activity and cytotoxicity(2004)34 cited
• → 2-Arylmethylaminomethyl-5,6-dihydroxychromone derivatives with selective anti-HCV activity(2011)11 cited
• → ChemInform Abstract: Alkyl Substituent Effect in the Deprotonation of Unsymmetrical Ketones(1996)
• → Influence of a β‐Alkoxy Substituent on the C—H Activation Chemistry of Alkyl Ethers.(2003)