AstraZeneca , Mereside, Alderley Park, Macclesfield SK10 4TG, U.K.
J Med Chem. 2014 Jul 24;57(14):6128-40. doi: 10.1021/jm500610n. Epub 2014 Jul 8.
Ghrelin plays a major physiological role in the control of food intake, and inverse agonists of the ghrelin receptor (GHS-R1a) are widely considered to offer utility as antiobesity agents by lowering the set-point for hunger between meals. We identified an acylurea series of ghrelin modulators from high throughput screening and optimized binding affinity through structure-activity relationship studies. Furthermore, we identified specific substructural changes, which switched partial agonist activity to inverse agonist activity, and optimized physicochemical and DMPK properties to afford the non-CNS penetrant inverse agonist 22 (AZ-GHS-22) and the CNS penetrant inverse agonist 38 (AZ-GHS-38). Free feeding efficacy experiments showed that CNS exposure was necessary to obtain reduced food intake in mice, and it was demonstrated using GHS-R1a null and wild-type mice that this effect operates through a mechanism involving GHS-R1a.
胃饥饿素在控制食物摄入方面起着重要的生理作用，胃饥饿素受体（GHS-R1a）的反向激动剂被广泛认为通过降低两餐之间的饥饿设定点来作为抗肥胖药物具有实用价值。我们从高通量筛选中鉴定出了一系列酰脲胃饥饿素调节剂，并通过构效关系研究优化了结合亲和力。此外，我们确定了特定的亚结构变化，将部分激动剂活性转换为反向激动剂活性，并优化了物理化学和 DMPK 性质，从而得到非 CNS 穿透性反向激动剂 22（AZ-GHS-22）和 CNS 穿透性反向激动剂 38（AZ-GHS-38）。自由喂养功效实验表明，CNS 暴露对于在小鼠中获得减少的食物摄入是必要的，并且使用 GHS-R1a 缺失和野生型小鼠证明了这一作用通过涉及 GHS-R1a 的机制发挥作用。
