Emmitte Kyle A
a Department of Pharmaceutical Sciences, UNT System College of Pharmacy , University of North Texas Health Science Center , Fort Worth , TX , USA.
Expert Opin Ther Pat. 2017 Jun;27(6):691-706. doi: 10.1080/13543776.2017.1280466. Epub 2017 Jan 19.
The pursuit of small molecule mGlu NAMs as treatments for a variety of psychiatric and neurodegenerative disorders has developed into a mature field. In addition to extensive preclinical studies, multiple compounds have advanced into clinical trials with the most advanced studies occurring in patients with FXS, PD-LID, and MDD. Areas covered: This review begins with an update of the clinical activity with mGlu NAMs, and then moves into a summary of patent applications filed since 2013. The summaries are organized into three separate sections: (1) inventions centered on improvements to existing clinical compounds; (2) new small molecules that maintain the prototypical disubstituted alkyne chemotype found in many mGlu NAM compounds; and (3) new small molecules that are not from a disubstituted alkyne chemotype. Expert opinion: It is a critical moment for mGlu NAM research as recent reports from clinical trials have included some significant disappointments that have blunted prior optimism. Still, research in this area remains active, and recent years have added several more attractive small molecules to this field. There is now an arsenal of diverse chemotypes available to continue to probe this target in the hopes that a drug may yet emerge.
将小分子代谢型谷氨酸受体负变构调节剂（mGlu NAMs）作为多种精神疾病和神经退行性疾病的治疗手段的研究已发展成为一个成熟的领域。除了广泛的临床前研究外，多种化合物已进入临床试验阶段，其中进展最为前沿的研究针对脆性X综合征（FXS）、帕金森病所致异动症（PD-LID）和重度抑郁症（MDD）患者。涵盖领域：本综述首先介绍mGlu NAMs的临床活性最新情况，然后总结自2013年以来提交的专利申请。这些总结分为三个独立部分：（1）以改进现有临床化合物为中心的发明；（2）保持许多mGlu NAM化合物中发现的典型双取代炔烃化学结构类型的新小分子；（3）非双取代炔烃化学结构类型的新小分子。专家观点：对于mGlu NAM研究而言，这是一个关键时刻，因为近期临床试验报告包含了一些重大挫折，削弱了之前的乐观情绪。尽管如此，该领域的研究依然活跃，近年来又有几种更具吸引力的小分子加入该领域。现在有多种化学结构类型可供继续探索这一靶点，以期最终能研发出一种药物。
