The Discovery of RGH-706, a Highly Efficacious MCH1 Receptor Antagonist, for the Treatment of Obesity and Insatiable Hunger

The discovery and characterization of a novel 2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,7-a]indole derivative MCH1 receptor antagonist (37) is disclosed. Starting from our previously investigated pyrazino[1,2-a]indole series and utilizing a scaffold hopping strategy, pyrimidine- and 1,4-diazepine-fused indole derivatives were designed and synthesized. Among these, only the prototype molecule containing the 2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,7-a]indole scaffold emerged as a chemically stable and potent MCHR1 antagonist. Previous SAR knowledge coupled with an ex vivo occupancy assay helped us to optimize this advanced lead to our candidate (37). The high MCHR1 potency and excellent receptor occupancy profile of 37 translated into statistically significant body weight loss after 14 days in a DIO mice study, supporting the potential use of this compound as a weight loss agent. Compound 37 (RGH-706) has successfully completed a phase I (SAD & MAD) clinical study in the indication of obesity, followed by an exploratory Phase II study in patients with Prader–Willi Syndrome (PWS).

本研究公开了一种新型2,3,4,5-四氢-1H-[1,4]二氮杂䓬并[1,7-a]吲哚类MCH1受体拮抗剂衍生物（化合物37）的发现与表征工作。本研究基于此前研发的吡嗪并[1,2-a]吲哚类系列化合物，采用骨架跃迁（scaffold hopping）策略，设计并合成了嘧啶并吲哚与1,4-二氮杂䓬并吲哚类衍生物。在该系列衍生物中，仅含2,3,4,5-四氢-1H-[1,4]二氮杂䓬并[1,7-a]吲哚骨架的原型分子展现出优异的化学稳定性与强效的MCHR1拮抗活性。既往构效关系（Structure-Activity Relationship, SAR）知识结合离体受体占位实验，助力我们将该优质先导化合物优化至候选化合物（37）。化合物37的高MCHR1拮抗活性与优异的受体占位特性，在饮食诱导肥胖（Diet-Induced Obesity, DIO）小鼠模型中给药14天后，可带来具有统计学显著性的体重降低，证实该化合物具备开发为减重药物的潜力。化合物37（代号RGH-706）已针对肥胖适应症顺利完成I期（单剂量递增Single Ascending Dose, SAD & 多剂量递增Multiple Ascending Dose, MAD）临床试验，随后针对普拉德-威利综合征（Prader–Willi Syndrome, PWS）患者开展了探索性II期临床试验。