Tucci Fabio C, White Nicole S, Markison Stacy, Joppa Margaret, Tran Joe A, Fleck Beth A, Madan Ajay, Dyck Brian P, Parker Jessica, Pontillo Joseph, Arellano L Melissa, Marinkovic Dragan, Jiang Wanlong, Chen Caroline W, Gogas Kathleen R, Goodfellow Val S, Saunders John, Foster Alan C, Chen Chen
Department of Medicinal Chemistry, Neurocrine Biosciences Inc., 12790 El Camino Real, San Diego, CA 92130, USA.
Bioorg Med Chem Lett. 2005 Oct 1;15(19):4389-95. doi: 10.1016/j.bmcl.2005.06.071.
The melanocortin-4 receptor (MC4R) plays an important role in the regulation of energy homeostasis. Recent studies have shown that blockade of the MC4R reverses tumor-induced weight loss in mice. Herein, we describe the synthesis and identification of potent and selective non-peptide antagonists of the human MC4R from a series of 2-ethoxycarbonylcyclohexyl-piperazines. Compound 12i was found to possess low nanomolar affinity for the MC4R, and exhibit oral bioavailability in rats. More importantly, when administered orally to mice (10 mg/kg), it led to statistically significant increases in food intake over a 24-h period.
黑皮质素-4受体（MC4R）在能量平衡调节中起重要作用。最近的研究表明，阻断MC4R可逆转小鼠肿瘤诱导的体重减轻。在此，我们描述了从一系列2-乙氧羰基环己基哌嗪中合成并鉴定出强效且选择性的人MC4R非肽拮抗剂。发现化合物12i对MC4R具有低纳摩尔亲和力，并在大鼠中表现出口服生物利用度。更重要的是，当以10mg/kg口服给予小鼠时，它在24小时内导致食物摄入量有统计学意义的增加。
