Chen Chen, Jiang Wanlong, Tran Joe A, Tucci Fabio C, Fleck Beth A, Markison Stacy, Wen Jenny, Madan Ajay, Hoare Sam R, Foster Alan C, Marinkovic Dragan, Chen Caroline W, Arellano Melissa, Saunders John
Department of Medicinal Chemistry, Neurocrine Biosciences, Inc., 12790 El Camino Real, San Diego, CA 92130, USA.
Bioorg Med Chem Lett. 2008 Jan 1;18(1):129-36. doi: 10.1016/j.bmcl.2007.10.115. Epub 2007 Nov 4.
A series of trans-4-phenylpyrrolidine-3-carboxamides were synthesized and characterized as potent ligands of the human melanocortin-4 receptor. Interestingly, a pair of diastereoisomers 13b displayed potent functional agonist and antagonist activity, respectively. Thus, the 3S,4R-pyrrolidine 13b-1 possessed a Ki of 1.0 nM and an EC50 of 3.8 nM, while its 3R,4S-isomer 13b-2 exhibited a Ki of 4.7 and an IC50 of 64 nM. Both compounds were highly selective over other melanocortin receptor subtypes. The MC4R agonist 13b-1 also demonstrated efficacy in a diet-induced obesity model in rats.
合成了一系列反式-4-苯基吡咯烷-3-甲酰胺，并将其表征为人类黑皮质素-4受体的有效配体。有趣的是，一对非对映异构体13b分别表现出强效的功能激动剂和拮抗剂活性。因此，3S,4R-吡咯烷13b-1的Ki为1.0 nM，EC50为3.8 nM，而其3R,4S-异构体13b-2的Ki为4.7，IC50为64 nM。这两种化合物对其他黑皮质素受体亚型具有高度选择性。MC4R激动剂13b-1在大鼠饮食诱导的肥胖模型中也显示出疗效。
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