229007-75-4Relevant academic research and scientific papers
Orally active CCR5 antagonists as anti-HIV-1 agents 2: Synthesis and biological activities of anilide derivatives containing a pyridine N-oxide moiety
Seto, Masaki,Aramaki, Yoshio,Imoto, Hiroshi,Aikawa, Katsuji,Oda, Tsuneo,Kanzaki, Naoyuki,Iizawa, Yuji,Baba, Masanori,Shiraishi, Mitsuru
, p. 818 - 829 (2004)
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 previoiusly reported quaternary ammonium moiety. Among these compounds, the 2-(α-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 (IC50=5.4 nM) in the fusion assay, together with good pharmacokinetic properties in rats.
Anilide derivative, production and use thereof
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, (2008/06/13)
This invention is to provide a compound of the formula: wherein R1 is an optionally substituted 5- to 6-membered ring: C is a divalent group of the formula: wherein the ring A is an optionally substituted 5- to 6-membered aromatic ring, X is an optionally substituted C, N or O atom, and the ring B is an optionally substituted 5- to 7-membered ring; Z is a chemical bond or a divalent group; R2 is (1) an optionally substituted amino group in which a nitrogen atom may form a quaternary ammonium, etc., or a salt thereof, which is useful for antagonizing MCP-1 receptor.
