Highly potent and orally active CCR5 antagonists as anti-HIV-1 agents: synthesis and biological activities of 1-benzazocine derivatives containing a sulfoxide moiety.
Chemical modification has been performed on an orally bioavailable and potent CCR5 antagonist, sulfoxide compound 4, mainly focusing on replacement of the [6,7]-fused 1-benzazepine nucleus. We designed, synthesized, and evaluated the biological activities of ring-expanded [6,8]-, [6,9]-, and [6,10]-fused compounds containing S-sulfoxide moieties, which led to the discovery of 1-benzazocine and 1-benzazonine compounds that exhibited potent inhibitory activities (equivalent to compound 4) in a binding assay. In addition, 1-benzazocine compounds possessing the S-sulfoxide moiety ((S)-(-)-5a,b,d,e) showed greater potency than compound 4 in a fusion assay. From further investigation in a multi-round infection assay, it was found that 1-isobutyl-1-benzazocine compound (S)-(-)-5b, containing the S-{[(1-propyl-1H-imidazol)-5-yl]methyl}sulfinyl group, showed the most potent anti-HIV-1 activity (IC90=0.81 nM, in MOLT4/CCR5 cells). Compound (S)-(-)-5b (TAK-652) also inhibited the replication of six macrophage-tropic (CCR5-using or R5) HIV-1 clinical isolates in peripheral blood mononuclear cells (PBMCs) (mean IC90=0.25 nM). It was also absorbed after oral administration in rats, dogs, and monkeys and was thus selected as a clinical candidate. The synthesis and biological activity of the 1-benzazocine compound (S)-(-)-5b and its related derivatives are described.
Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 2-17-85 Jusohonmachi, Yodogawa-ku, Osaka 532-8686, Japan. Seto_Masaki@takeda.co.jp
Masaki
M
Seto
Katsuji
K
Aikawa
Naoki
N
Miyamoto
Yoshio
Y
Aramaki
Naoyuki
N
Kanzaki
Katsunori
K
Takashima
Yoji
Y
Kuze
Yuji
Y
Iizawa
Masanori
M
Baba
Mitsuru
M
Shiraishi
D000284:Administration, Oral; D000818:Animals; D019380:Anti-HIV Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001392:Azocines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001682:Biological Availability; D065100:CCR5 Receptor Antagonists; D002460:Cell Line; D002522:Chlorocebus aethiops; D004285:Dogs; D015699:HIV Envelope Protein gp120 / Q000502:physiology; D015497:HIV-1 / Q000187:drug effects* / Q000302:isolation & purification; D006207:Half-Life; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D066298:In Vitro Techniques; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000821:virology; D008252:Macaca fascicularis; D008297:Male; D008561:Membrane Fusion / Q000187:drug effects; D051381:Rats; D013237:Stereoisomerism; D013454:Sulfoxides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014779:Virus Replication / Q000187:drug effects
D019380:Anti-HIV Agents; D001392:Azocines; D065100:CCR5 Receptor Antagonists; D015699:HIV Envelope Protein gp120; D007093:Imidazoles; D013454:Sulfoxides; C506967:cenicriviroc