title: Orally active CCR5 antagonists as anti-HIV-1 agents 2: synthesis and biological activities of anilide derivatives containing a pyridine N-oxide moiety.
abstract: In order to develop orally active CCR5 antagonists, we investigated 1-benzoxepine derivatives containing new polar substituents, such as phosphonate, phosphine oxide or pyridine N-oxide moieties, as replacements for the previously reported quaternary ammonium moiety. Among these compounds, the 2-(alpha-hydroxybenzyl)pyridine N-oxide 5e exhibited moderate CCR5 antagonistic activity and had an acceptable pharmacokinetic profile in rats. Subsequent chemical modification was performed and compound (S)-5f possessing the (S)-configuration hydroxy group was found to be more active than the (R)-isomer. Replacement of the 1-benzoxepine ring with a 4-methylphenyl group by a 1-benzazepine ring with a 4-[2-(butoxy)ethoxy]phenyl group enhanced the activity in the binding assay. In addition, introduction of a 3-trifluoromethyl group on the phenyl group of the anilide moiety led to greatly increased activity in the HIV-1 envelope-mediated membrane fusion assay. In particular, compound (S)-5s showed the most potent CCR5 antagonistic activity (IC(50)=7.2 nM) and inhibitory effect (IC(50)=5.4 nM) in the fusion assay, together with good pharmacokinetic properties in rats.
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: Hiroshi
authors.initials: H
authors.lastname: Imoto
authors.forename: Katsuji
authors.initials: K
authors.lastname: Aikawa
authors.forename: Tsuneo
authors.initials: T
authors.lastname: Oda
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Kanzaki
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; D000813:Anilides / Q000008:administration & dosage* / Q000138:chemical synthesis / Q000378:metabolism; D000818:Animals; D019380:Anti-HIV Agents / Q000008:administration & dosage* / Q000138:chemical synthesis / Q000378:metabolism; D065100:CCR5 Receptor Antagonists; D016466:CHO Cells; D002522:Chlorocebus aethiops; D006224:Cricetinae; D015497:HIV-1 / Q000187:drug effects* / Q000378:metabolism; D011485:Protein Binding / Q000502:physiology; D011725:Pyridines / Q000008:administration & dosage* / Q000737:chemistry / Q000378:metabolism; D019713:Receptors, CCR5 / Q000378:metabolism
chemical_list: D000813:Anilides; D019380:Anti-HIV Agents; D065100:CCR5 Receptor Antagonists; D011725:Pyridines; D019713:Receptors, CCR5; C013229:pyridine N-oxide