Rational Design, Synthesis, and Pharmacological Characterization of Novel Ghrelin Receptor Inverse Agonists as Potential Treatment against Obesity-Related Metabolic Diseases

A new chemotype of ghrelin inverse agonists was discovered through chimeric design based on molecular scaffolds known as growth-hormone secretagogue receptor (GHSR) modulators but with divergent pharmacodynamic and pharmacokinetic properties. The structure–activities/properties exploration led to compound 47, which displayed potent human GHSR antagonism and inverse agonism in cellular assays (IC50 = 68 nM, EC50 = 29 nM), moderate oral bioavailability, and notable brain penetration in rat (F = 27%, B/P ratio = 1.9). First in vivo studies demonstrated effective reduction of food intake after oral or parenteral administration to mouse (78% at 1 h and 38% at 8 h, respectively). Further preclinical studies are needed to evaluate the most suited mode of administration with the aim of promoting a first central-acting ghrelin inverse agonist molecule to development, which would represent a significant step toward therapeutic agents to treat metabolic disorders related to obesity, such as type 2 diabetes mellitus.本研究以生长激素促分泌素受体（growth-hormone secretagogue receptor, GHSR）调节剂的分子骨架为基础，通过嵌合设计策略发现了一类新型饥饿素（ghrelin）反向激动剂化学型，该类化合物相较于传统GHSR调节剂具有差异化的药效动力学与药代动力学属性。通过构效/构性关系研究，最终筛选得到化合物47。该化合物在细胞实验中展现出强效的人源GHSR拮抗活性与反向激动活性（半最大抑制浓度IC50=68 nM，半最大有效浓度EC50=29 nM），具备中等水平的口服生物利用度，且在大鼠体内展现出显著的血脑屏障穿透性（绝对生物利用度F=27%，脑/血浆浓度比B/P=1.9）。首批体内实验结果显示，对小鼠进行口服或胃肠外给药后，该化合物可有效降低其摄食量：给药1小时后摄食量抑制率达78%，8小时后达38%。后续需开展更多临床前研究以评估最优给药方式，旨在推动首款中枢作用型饥饿素反向激动剂进入开发阶段；该类药物若能成功研发，将为治疗肥胖相关代谢紊乱（如2型糖尿病）的治疗药物开发迈出重要一步。