Orally active CCR5 antagonists as anti-HIV-1 agents. Part 3: Synthesis and biological activities of 1-benzazepine derivatives containing a sulfoxide moiety.
In order to develop orally active CCR5 antagonists, 1-propyl- or 1-isobutyl-1-benzazepine derivatives containing a sulfoxide moiety have been designed, synthesized, and evaluated for their biological activities. Sulfoxide compounds containing a 2-pyridyl group were first investigated, which led to discovering that the presence of a methylene group between the sulfoxide moiety and 2-pyridyl group was necessary for increased inhibitory activity in a binding assay. After further chemical modification, it was found that replacement of the pyridyl group with an imidazolyl or 1,2,4-triazolyl group enhanced activity in the binding assay and that S-sulfoxide compounds were more active than R-isomers. Particularly, compounds (S)-4r, (S)-4s, and (S)-4w exhibited highly potent CCR5 antagonistic activities (IC50=1.9, 1.7, 1.6 nM, respectively) and inhibitory effects (IC50=1.0, 2.8, 7.7 nM, respectively) in the HIV-1 envelope mediated membrane fusion assay, together with good pharmacokinetic properties in rats. In addition, we established the synthesis of (S)-4r and (S)-4w by asymmetric oxidation with titanium-(S)-(-)-1,1'-bi-2-naphthol complex.
Seto
Masaki
M
Pharmaceutical Research Division, Takeda Pharmaceutical Company, Ltd., 2-17-85 Jusohonmachi,Yodogawa-ku, Osaka 532-8686, Japan. seto_masaki@takeda.co.jp
Miyamoto
Naoki
N
Aikawa
Katsuji
K
Aramaki
Yoshio
Y
Kanzaki
Naoyuki
N
Iizawa
Yuji
Y
Baba
Masanori
M
Shiraishi
Mitsuru
M
D000818:Animals; D019380:Anti-HIV Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D001552:Benzazepines / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D065100:CCR5 Receptor Antagonists; D016466:CHO Cells; D019556:COS Cells; D002522:Chlorocebus aethiops; D006224:Cricetinae; D003412:Cricetulus; D015195:Drug Design; D015497:HIV-1 / Q000187:drug effects; D006801:Humans; D008297:Male; D008956:Models, Chemical; D008958:Models, Molecular; D015394:Molecular Structure; D051381:Rats; D019713:Receptors, CCR5 / Q000737:chemistry; D013329:Structure-Activity Relationship
D019380:Anti-HIV Agents; D001552:Benzazepines; D065100:CCR5 Receptor Antagonists; D019713:Receptors, CCR5