Design and Synthesis of Clinical Candidate PF-06852231 (CVL-231): A Brain Penetrant, Selective, Positive Allosteric Modulator of the M4 Muscarinic Acetylcholine Receptor

Selective activation of the M4 muscarinic
acetylcholine
receptor subtype offers a novel strategy for the treatment of psychosis
in multiple neurological disorders. Although the development of traditional
muscarinic activators has been stymied due to pan-receptor activation,
muscarinic receptor subtype selectivity can be achieved through the
utilization of a subtype of a unique allosteric site. A major challenge
in capitalizing on this allosteric site to date has been achieving
a balance of suitable potency and brain penetration. Herein, we describe
the design of a brain penetrant series of M4 selective
positive allosteric modulators (PAMs), ultimately culminating in the
identification of 21 (PF-06852231, now CVL-231/emraclidine),
which is under active clinical development as a novel mechanism and
approach for the treatment of schizophrenia.

选择性激活M4型毒蕈碱乙酰胆碱受体亚型，为多发性神经系统疾病中精神病的治疗提供了一种新颖的策略。尽管由于广泛的受体激活，传统毒蕈碱激动剂的研发受到了阻碍，但通过利用独特的别构位点的一个亚型，可以实现毒蕈碱受体亚型的选择性。截至目前，利用这一别构位点的主要挑战在于实现适宜的活性和脑渗透性的平衡。本文中，我们描述了一系列具有脑渗透性的M4选择性正别构调节剂（PAMs）的设计，最终识别出21种（PF-06852231，现CVL-231/emraclidine），该药物正处于积极的临床开发阶段，作为治疗精神分裂症的一种新型机制和方法。