Antagonists of human CCR5 receptor containing 4-(pyrazolyl)piperidine side chains. Part 2: Discovery of potent, selective, and orally bioavailable compounds

• Published in: Bioorganic & medicinal chemistry letters Vol. 14; no. 4; pp. 941 - 945
• Main Authors: SHEN, Dong-Ming, MIN SHU, GOULD, Sandra L, DEMARTINO, Julie A, SICILIANO, Salvatore J, LYONS, Kathy, PIVNICHNY, James V, KWEI, Gloria Y, CARELLA, Anthony, CARVER, Gwen, HOLMES, Karen, SCHLEIF, William A, WILLOUGHBY, Christopher A, DANZEISEN, Renee, HAZUDA, Daria, KESSLER, Joseph, LINEBERGER, Janet, MILLER, Michael D, EMINI, Emilio A, SHAH, Shrenik, LYNCH, Christopher L, HALE, Jeffrey J, MILLS, Sander G, CHAPMAN, Kevin T, MALKOWITZ, Lorraine, SPRINGER, Martin S
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier 23-02-2004
• Subjects: Acetates - chemistry; Acetates - pharmacokinetics; Administration, Oral; Animals; Anti-HIV Agents - chemical synthesis; Anti-HIV Agents - chemistry; Anti-HIV Agents - pharmacokinetics; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiviral agents; Biological and medical sciences; Biological Availability; CCR5 Receptor Antagonists; Dogs; HeLa Cells; Humans; Macaca mulatta; Medical sciences; Molecular Structure; Monocytes - drug effects; Pharmacology. Drug treatments; Piperidines - chemical synthesis; Piperidines - chemistry; Piperidines - pharmacokinetics; Pyrazoles - chemistry; Pyrazoles - pharmacokinetics; Rats; Structure-Activity Relationship; HIV-1 virus; Nitrogen heterocycle; Monkey; Selectivity; Pyrrolidine derivatives; Structure activity relation; Piperidine derivatives; Primates; Pyrazole derivatives; Antiviral; Antagonist; Chemical synthesis; Dog; Fissipedia; Carnivora; Oral administration; Retroviridae; Bioavailability; Lentivirus; In vitro; Virus; CCR5 chemokine receptor; Vertebrata; Mammalia; Side chain; Animal; Human immunodeficiency virus; Fluorine Organic compounds; Pharmacokinetics
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2003.12.005

Modifications of the alkyl acetic acid portion and the phenyl on pyrrolidine in our lead pyrazole compound 1 afforded the isopropyl compound 9. This compound is a potent CCR5 antagonist showing good in vitro antiviral activity against HIV-1, an excellent selectivity profile, and good oral bioavailability in three animal species. During this investigation, a new method for the preparation of alpha-(pyrrolidin-1-yl)-alpha,alpha-dialkyl acetic acid from a pyrrolidine and alpha-bromo-alpha,alpha-dialkyl acetic acid using silver triflate was discovered. This allowed us to prepare compounds such as 24 and 25 for the first time. A novel Pd-mediated N-dealkylation of alpha-(pyrrolidin-1-yl)acetic acid was also uncovered.