title: Discovery of novel pyridyl carboxamides as potent CCR5 antagonists and optimization of their pharmacokinetic profile in rats.
abstract: A novel series of pyridyl carboxamide-based CCR5 inhibitors was designed, synthesized, and demonstrated to be highly potent against HIV-1 infection in both HOS and PBL assays. Attempts to evaluate this series of compounds in a rat PK model revealed its instability in rat plasma. A hypothesis for this liability was proposed, and strategies to overcome this issue were pursued, leading to discovery of highly potent 40 and 41, which featured dramatically improved rat PK profiles.
authors.affiliation: Infectious Disease Medicine Discovery & Development, GlaxoSmithKline, Five Moore Drive, Research Triangle Park, NC 27706, USA. duanmaosheng@hdbiosciences.com
authors.forename: Maosheng
authors.initials: M
authors.lastname: Duan
authors.forename: Wieslaw M
authors.initials: WM
authors.lastname: Kazmierski
authors.forename: Pek Y
authors.initials: PY
authors.lastname: Chong
authors.forename: Felix
authors.initials: F
authors.lastname: Deanda
authors.forename: Mark
authors.initials: M
authors.lastname: Edelstein
authors.forename: Rob
authors.initials: R
authors.lastname: Ferris
authors.forename: Jennifer
authors.initials: J
authors.lastname: Peckham
authors.forename: Pat
authors.initials: P
authors.lastname: Wheelan
authors.forename: Zhiping
authors.initials: Z
authors.lastname: Xiong
authors.forename: Huichang
authors.initials: H
authors.lastname: Zhang
authors.forename: Rena
authors.initials: R
authors.lastname: Nishizawa
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Takaoka
mesh_terms: D000577:Amides / Q000737:chemistry; D000818:Animals; D019380:Anti-HIV Agents / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D065100:CCR5 Receptor Antagonists; D002264:Carboxylic Acids / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D055808:Drug Discovery; D051381:Rats
chemical_list: D000577:Amides; D019380:Anti-HIV Agents; D065100:CCR5 Receptor Antagonists; D002264:Carboxylic Acids