title: Discovery of novel, potent, and selective small-molecule CCR5 antagonists as anti-HIV-1 agents: synthesis and biological evaluation of anilide derivatives with a quaternary ammonium moiety.
abstract: The search for new small-molecule CCR5 antagonists by high-throughput screening (HTS) of the Takeda chemical library using [(125)I]RANTES and CHO/CCR5 cells led to the discovery of lead compounds (A, B) with a quaternary ammonium or phosphonium moiety, which were synthesized to investigate new MCP-1 receptor antagonists. A series of novel anilide derivatives 1 with a quaternary ammonium moiety were designed, synthesized, and tested for their CCR5 antagonistic activity. Through the optimization of lead compounds, we have found N,N-dimethyl-N-[4-[[[2-(4-methylphenyl)-6, 7-dihydro-5H-benzocyclohepten-8-yl]carbonyl]amino]benzyl]tetrahydr o-2 H-pyran-4-aminium chloride (1r, TAK-779) as a highly potent and selective nonpeptide CCR5 antagonist with a IC(50) value of 1.4 nM in the binding assay. Compound 1r also inhibited the replication of macrophage (M)-tropic HIV-1 (Ba-L strain) in both MAGI-CCR5 cells and PBMCs with EC(50) values of 1.2 and 3.7 nM, respectively. The synthesis and structure-activity relationships of 1r and its related compounds are detailed.
authors.affiliation: Pharmaceutical Research Division and Discovery Research Division, Takeda Chemical Industries, Ltd., 2-17-85, Jusohonmachi, Yodogawa-ku, Osaka 532-8686, Japan. Shiraishi_Mitsuru@takeda.co.jp
authors.forename: M
authors.initials: M
authors.lastname: Shiraishi
authors.forename: Y
authors.initials: Y
authors.lastname: Aramaki
authors.forename: M
authors.initials: M
authors.lastname: Seto
authors.forename: H
authors.initials: H
authors.lastname: Imoto
authors.forename: Y
authors.initials: Y
authors.lastname: Nishikawa
authors.forename: N
authors.initials: N
authors.lastname: Kanzaki
authors.forename: M
authors.initials: M
authors.lastname: Okamoto
authors.forename: H
authors.initials: H
authors.lastname: Sawada
authors.forename: O
authors.initials: O
authors.lastname: Nishimura
authors.forename: M
authors.initials: M
authors.lastname: Baba
authors.forename: M
authors.initials: M
authors.lastname: Fujino
mesh_terms: D000577:Amides / Q000138:chemical synthesis* / Q000494:pharmacology; D000818:Animals; D019380:Anti-HIV Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D065100:CCR5 Receptor Antagonists; D016466:CHO Cells; D002460:Cell Line; D054413:Chemokine CCL11; D018932:Chemokine CCL2 / Q000378:metabolism; D018946:Chemokine CCL5 / Q000378:metabolism; D019742:Chemokines, CC / Q000378:metabolism; D006224:Cricetinae; D016207:Cytokines / Q000378:metabolism; D015497:HIV-1 / Q000187:drug effects*; D007457:Iodine Radioisotopes; D008264:Macrophages / Q000821:virology; D015394:Molecular Structure; D000644:Quaternary Ammonium Compounds / Q000138:chemical synthesis* / Q000494:pharmacology; D019713:Receptors, CCR5 / Q000378:metabolism; D013329:Structure-Activity Relationship; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000577:Amides; D019380:Anti-HIV Agents; D065100:CCR5 Receptor Antagonists; D054413:Chemokine CCL11; D018932:Chemokine CCL2; D018946:Chemokine CCL5; D019742:Chemokines, CC; D016207:Cytokines; D007457:Iodine Radioisotopes; D000644:Quaternary Ammonium Compounds; D019713:Receptors, CCR5; C119369:TAK 779