title: 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.
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.
authors.affiliation: Medicinal Chemistry Research Laboratries, Pharmaceutical Research Division, Takeda Chemical Industries Ltd., Osaka, Japan. Seto_Masaki@takeda.co.jp
authors.forename: Masaki
authors.initials: M
authors.lastname: Seto
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Aramaki
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Okawa
authors.forename: Naoki
authors.initials: N
authors.lastname: Miyamoto
authors.forename: Katsuji
authors.initials: K
authors.lastname: Aikawa
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Kanzaki
authors.forename: Shin-Ichi
authors.initials: S
authors.lastname: Niwa
authors.forename: Yuji
authors.initials: Y
authors.lastname: Iizawa
authors.forename: Masanori
authors.initials: M
authors.lastname: Baba
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Shiraishi
mesh_terms: D000284:Administration, Oral; D000588:Amines / Q000008:administration & dosage / Q000138:chemical synthesis / Q000378:metabolism; D000818:Animals; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000378:metabolism; D001552:Benzazepines / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000378:metabolism; D001582:Benzothiepins / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000378:metabolism; D065100:CCR5 Receptor Antagonists; D016466:CHO Cells; D019556:COS Cells; D002522:Chlorocebus aethiops; D006224:Cricetinae; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D019713:Receptors, CCR5 / Q000378:metabolism
chemical_list: D000588:Amines; D019380:Anti-HIV Agents; D001552:Benzazepines; D001582:Benzothiepins; D065100:CCR5 Receptor Antagonists; D019713:Receptors, CCR5