Department of Medicinal Chemistry, Merck Research Laboratories, Rahway, NJ 07065, USA.
Bioorg Med Chem Lett. 2010 Apr 1;20(7):2354-8. doi: 10.1016/j.bmcl.2010.01.120. Epub 2010 Feb 1.
A new class of potent NK(1) receptor antagonists with a tetrahydroindolizinone core has been identified. This series of compounds demonstrated improved functional activities as compared to previously identified 5,5-fused pyrrolidine lead structures. SAR at the 7-position of the tetrahydroindolizinone core is discussed in detail. A number of compounds displayed high NK(1) receptor occupancy at both 1 h and 24 h in a gerbil foot tapping model. Compound 40 has high NK(1) binding affinity, good selectivity for other NK receptors and promising in vivo properties. It also has clean P(450) inhibition and hPXR induction profiles.
一种新型的强效 NK(1)受体拮抗剂，具有四氢吲哚嗪酮核心，已经被鉴定出来。与之前鉴定的 5,5-稠合吡咯烷先导结构相比，这一系列化合物表现出改善的功能活性。详细讨论了四氢吲哚嗪酮核心 7 位的 SAR。在沙土鼠足叩击模型中，许多化合物在 1 小时和 24 小时时均显示出高 NK(1)受体占有率。化合物 40 具有高 NK(1)结合亲和力，对其他 NK 受体具有良好的选择性，并且具有有前景的体内特性。它还具有清洁的 P(450)抑制和 hPXR 诱导特性。
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