title: CCR5 antagonists as anti-HIV-1 agents. 1. Synthesis and biological evaluation of 5-oxopyrrolidine-3-carboxamide derivatives.
abstract: A novel lead compound, N-(3-[4-(4-fluorobenzoyl)piperidin-1-yl]propyl)-1-methyl-5-oxo-N-phenylpyrrolidine-3-carboxamide (1), was identified as a CCR5 antagonist by high-throughput screening using [(125)I]RANTES and CCR5-expressing CHO cells. The IC(50) value of 1 was 1.9 microM. In an effort to improve the binding affinity of 1, a series of 5-oxopyrrolidine-3-carboxamides was synthesized. Introduction of 3,4-dichloro substituents to the central phenyl ring (10i, IC(50)=0.057 microM; 11b, IC(50)=0.050 microM) or replacing the 1-methyl group of the 5-oxopyrrolidine moiety with a 1-benzyl group (12e, IC(50)=0.038 microM) was found to be effective for improving CCR5 affinity. Compound 10i, 11b, and 12e also inhibited CCR5-using HIV-1 envelope-mediated membrane fusion with IC(50) values of 0.44, 0.19, and 0.49 microM, respectively.
authors.affiliation: Pharmaceutical Research Division, Takeda Chemical Industries Ltd., 2-17-85 Jusohonmachi, Yodogawa-ku, Osaka 532-8686, Japan. Imamura_Shin-ichi@takeda.co.jp
authors.forename: Shinichi
authors.initials: S
authors.lastname: Imamura
authors.forename: Yuji
authors.initials: Y
authors.lastname: Ishihara
authors.forename: Taeko
authors.initials: T
authors.lastname: Hattori
authors.forename: Osamu
authors.initials: O
authors.lastname: Kurasawa
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Matsushita
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Sugihara
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Kanzaki
authors.forename: Yuji
authors.initials: Y
authors.lastname: Iizawa
authors.forename: Masanori
authors.initials: M
authors.lastname: Baba
authors.forename: Shohei
authors.initials: S
authors.lastname: Hashiguchi
mesh_terms: D000577:Amides / Q000737:chemistry* / Q000494:pharmacology*; D000818:Animals; D019380:Anti-HIV Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D065100:CCR5 Receptor Antagonists; D016466:CHO Cells; D019556:COS Cells; D018946:Chemokine CCL5 / Q000037:antagonists & inhibitors; D002522:Chlorocebus aethiops; D006224:Cricetinae; D004353:Drug Evaluation, Preclinical; D005260:Female; D015497:HIV-1 / Q000187:drug effects; D006801:Humans; D007202:Indicators and Reagents; D009682:Magnetic Resonance Spectroscopy; D010880:Piperidines / Q000737:chemistry / Q000494:pharmacology; D011759:Pyrrolidines / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: C488445:5-oxopyrrolidine-3-carboxamide; D000577:Amides; D019380:Anti-HIV Agents; D065100:CCR5 Receptor Antagonists; D018946:Chemokine CCL5; D007202:Indicators and Reagents; D010880:Piperidines; D011759:Pyrrolidines