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Article

Highly Potent and Orally Active CCR5 Antagonists as Anti-HIV-1 Agents: Synthesis and Biological Activities of 1-Benzazocine Derivatives Containing a Sulfoxide Moiety

Supporting Info

Masaki Seto,*^† Katsuji Aikawa,^† Naoki Miyamoto,^† Yoshio Aramaki,^† Naoyuki Kanzaki,^† Katsunori Takashima,^† Yoji Kuze,^† Yuji Iizawa,^† Masanori Baba,^‡ and Mitsuru Shiraishi^†

Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 2-17-85 Jusohonmachi, Yodogawa-ku, Osaka 532-8686, Japan, and Division of Antiviral Chemotherapy, Center for Chronic Viral Diseases, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1, Sakuragaoka, Kagoshima 890-8544, Japan

J. Med. Chem., 2006, 49 (6), pp 2037–2048

DOI: 10.1021/jm0509703

Publication Date (Web): March 1, 2006

Corresponding author. Tel: +81-6-6300-6651. Fax: +81-6-6300-6306. E-mail: Seto_Masaki@takeda.co.jp.

†

Takeda Pharmaceutical Company Limited.

‡

Kagoshima University.

Abstract

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.