含4-(吡唑基)哌啶侧链的人CCR5受体拮抗剂。第3部分：苄基吡唑片段的构效关系研究。
Antagonists of human CCR5 receptor containing 4-(pyrazolyl)piperidine side chains. Part 3: SAR studies on the benzylpyrazole segment.
作者信息
Shu Min, Loebach Jennifer L, Parker Kerry A, Mills Sander G, Chapman Kevin T, Shen Dong-Ming, Malkowitz Lorraine, Springer Martin S, Gould Sandra L, DeMartino Julie A, Siciliano Salvatore J, Salvo Jerry Di, Lyons Kathy, Pivnichny James V, 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
机构信息
Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065, USA.
出版信息
Bioorg Med Chem Lett. 2004 Feb 23;14(4):947-52. doi: 10.1016/j.bmcl.2003.12.006.
Extensive SAR studies in our benzylpyrazole series of CCR5 antagonists have shown that both lipophilic and hydrophilic substituents on the phenyl of the benzyl group increase antiviral potency. However, improvements in pharmacokinetic profiles were generally only observed with more lipophilic substitutions. 4-Biphenyl (51) performed the best in this regard. Highly lipophilic substituents impart undesirable ion channel activity to these CCR5 antagonists. Alkoxy substituents provide a good balance of antiviral activity, pharmacokinetic parameters, and selectivity. Compounds 42b and 42d, containing a 3,4-dimethoxy substituent, are considered the most promising improvements over parent compounds 9. They demonstrate improved antiviral activity while retaining good pharmacokinetic profile and selectivity.
我们对苄基吡唑系列CCR5拮抗剂进行了广泛的构效关系（SAR）研究，结果表明，苄基苯基上的亲脂性和亲水性取代基均可提高抗病毒活性。然而，一般只有亲脂性更强的取代基才能改善药代动力学特征。在这方面，4-联苯基（51）表现最佳。高度亲脂性取代基会赋予这些CCR5拮抗剂不良的离子通道活性。烷氧基取代基在抗病毒活性、药代动力学参数和选择性之间提供了良好的平衡。含有3,4-二甲氧基取代基的化合物42b和42d被认为是相对于母体化合物9最有前景的改进。它们在保持良好药代动力学特征和选择性的同时，抗病毒活性有所提高。
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