Discovery of novel pyridyl carboxamides as potent CCR5 antagonists and optimization of their pharmacokinetic profile in rats |
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| Authors: | Duan Maosheng Kazmierski Wieslaw M Chong Pek Y Deanda Felix Edelstein Mark Ferris Rob Peckham Jennifer Wheelan Pat Xiong Zhiping Zhang Huichang Nishizawa Rena Takaoka Yoshikazu |
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| Affiliation: | Infectious Disease Medicine Discovery & Development, GlaxoSmithKline, Five Moore Drive, Research Triangle Park, NC 27706, USA. duanmaosheng@hdbiosciences.com |
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| 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. |
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| Keywords: | Pyridyl carboxamide CCR5 Antagonist Pharmacokinetics HIV-1 Chemokine |
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