Shen Dong-Ming, Shu Min, Mills Sander G, Chapman Kevin T, Malkowitz Lorraine, Springer Martin S, Gould Sandra L, DeMartino Julie A, Siciliano Salvatore J, Kwei Gloria Y, Carella Anthony, Carver Gwen, Holmes Karen, Schleif William A, Danzeisen Renee, Hazuda Daria, Kessler Joseph, Lineberger Janet, Miller Michael D, Emini Emilio A
Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065, USA.
Bioorg Med Chem Lett. 2004 Feb 23;14(4):935-9. doi: 10.1016/j.bmcl.2003.12.004.
Replacement of the flexible connecting chains between the piperidine moiety and an aromatic group in previous CCR5 antagonists with heterocycles, such as pyrazole and isoxazole, provided potent CCR5 antagonists with excellent anti-HIV-1 activity in vitro. SAR studies revealed optimal placement of an unsubstituted nitrogen atom in the heterocycle to be meta to the bond connected to the 4-position of piperidine. Truncation of a benzyl group to a phenyl group afforded compounds with dramatically improved oral bioavailability, albeit with reduced activity.
用吡唑和异恶唑等杂环取代先前CCR5拮抗剂中哌啶部分与芳基之间的柔性连接链，得到了在体外具有优异抗HIV-1活性的强效CCR5拮抗剂。构效关系研究表明，杂环中未取代的氮原子最佳位置是与哌啶4位相连键的间位。将苄基截短为苯基得到了口服生物利用度显著提高的化合物，尽管活性有所降低。
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