Antagonists of the human CCR5 receptor as anti-HIV-1 agents. Part 1: Discovery and initial structure-activity relationships for 1-amino-2-phenyl-4-(piperidin-1-yl)butanes

• Published in: Bioorganic & medicinal chemistry letters Vol. 11; no. 2; pp. 259 - 264
• Main Authors: DORN, Conrad P, FINKE, Paul E, DEMARTINO, Julie A, SICILIANO, Salvatore J, CARELLA, Anthony, CARVER, Gwen, HOLMES, Karen, DANZEISEN, Renee, HAZUDA, Daria, KESSLER, Joseph, LINEBERGER, Janet, MILLER, Michael, OATES, Bryan, SCHLEIF, William A, EMINI, Emilio A, BUDHU, Richard J, MILLS, Sander G, MACCOSS, Malcolm, MALKOWITZ, Lorraine, SPRINGER, Martin S, DAUGHERTY, Bruce L, GOULD, Sandra L
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier 22-01-2001
• Subjects: Animals; Anti-HIV Agents - chemical synthesis; Anti-HIV Agents - chemistry; Anti-HIV Agents - metabolism; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiviral agents; Biological and medical sciences; CCR5 Receptor Antagonists; Chemokine CCL4; CHO Cells; Combinatorial Chemistry Techniques; Cricetinae; Humans; Inhibitory Concentration 50; Macrophage Inflammatory Proteins - metabolism; Medical sciences; Pharmacology. Drug treatments; Piperidines - chemical synthesis; Piperidines - chemistry; Piperidines - metabolism; Protein Binding; Receptors, CCR5 - genetics; Receptors, CCR5 - metabolism; Structure-Activity Relationship; Transfection; Sulfur nitrogen heterocycle; Sulfonamide; HIV-1 virus; Retroviridae; Tricyclic compound; Lentivirus; In vitro; Spiran; Virus; Chemokine; Biological fixation; Structure activity relation; Chlorine Organic compounds; Sulfoxide; Antiviral; Aromatic compound; Human immunodeficiency virus; Chemical synthesis; Biological receptor
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/S0960-894X(00)00637-5

Screening of the Merck sample collection for compounds with CCR5 receptor binding afforded (2S)-2-(3,4-dichlorophenyl)-1-[N-(methyl)-N-(phenylsulfonyl)amino]-4-[spiro(2,3-dihydrobenzthiophene-3,4'-piperidin-1'-yl)]butane S-oxide (4) as a potent lead structure having an IC50 binding affinity of 35 nM. Herein, we describe the discovery of this lead structure and our initial structure activity relationship studies directed toward the requirement for and optimization of the 1-amino fragment.