Research & Development, Bristol-Myers Squibb Co, PO Box 4000, Princeton, NJ 08543, United States.
Bioorg Med Chem Lett. 2010 Feb 1;20(3):1128-33. doi: 10.1016/j.bmcl.2009.12.014. Epub 2009 Dec 6.
Agonists of the 5-HT(2C) receptor have been shown to suppress appetite and reduce body weight in animal models as well as in humans. However, agonism of the related 5-HT(2B) receptor has been associated with valvular heart disease. Synthesis and biological evaluation of a series of novel and highly selective dihydroquinazolinone-derived 5-HT(2C) agonists with no detectable agonism of the 5-HT(2B) receptor is described. Among these, compounds (+)-2a and (+)-3c were identified as potent and highly selective agonists which exhibited weight loss in a rat model upon oral dosing.
5-HT(2C) 受体激动剂已被证明可抑制动物模型和人类的食欲并减轻体重。然而，相关的 5-HT(2B) 受体激动作用与心脏瓣膜病有关。本文描述了一系列新型高选择性二氢喹唑啉酮衍生 5-HT(2C) 激动剂的合成和生物学评价，这些化合物对 5-HT(2B) 受体没有可检测到的激动作用。在这些化合物中，(+)-2a 和 (+)-3c 被鉴定为具有口服给药可在大鼠模型中减轻体重的效力和高度选择性的激动剂。
