Julie L Engers, Jinming Li, Changho Han, Madeline F Long, Alison R Gregro, Christopher C Presley, Jonathan W Dickerson, Weimin Peng, Hyekyung P Cho, Alice L Rodriguez, Zixiu Xiang, Olivier Boutaud, Colin O'Carroll, P Markus Dey, Ethan S Burstein, Colleen M Niswender, Jerri M Rook, P Jeffrey Conn, Darren W Engers, Craig W Lindsley
{"title":"Application of Deuterium in an M<sub>1</sub> Positive Allosteric Modulator Back-Up Program: The Discovery of VU6045422.","authors":"Julie L Engers, Jinming Li, Changho Han, Madeline F Long, Alison R Gregro, Christopher C Presley, Jonathan W Dickerson, Weimin Peng, Hyekyung P Cho, Alice L Rodriguez, Zixiu Xiang, Olivier Boutaud, Colin O'Carroll, P Markus Dey, Ethan S Burstein, Colleen M Niswender, Jerri M Rook, P Jeffrey Conn, Darren W Engers, Craig W Lindsley","doi":"10.1021/acschemneuro.5c00119","DOIUrl":null,"url":null,"abstract":"<p><p>Recently, we disclosed VU0467319, an M<sub>1</sub> positive allosteric modulator (PAM) clinical candidate that had successfully completed a phase I single ascending dose clinical trial. Pharmacokinetic assessment revealed that, in humans upon increasing dose, a circulating, inactive metabolite constituted a major portion of the total drug-related area under the curve (AUC). One approach the team employed to reduce inactive metabolite formation in the back-up program was the kinetic isotope effect, replacing the metabolically labile C-H bonds with shorter, more stable C-D bonds. The C-D dipole afforded VU6045422, a more potent M<sub>1</sub> PAM (human EC<sub>50</sub> = 192 nM, 80% ACh Max) than its proteocongener VU0467319 (human EC<sub>50</sub> = 492 nM, 71% ACh Max), and retained the desired profile of minimal M<sub>1</sub> agonism. Overall, the profile of VU6045422 supported advancement, as did greater <i>in vitro</i> metabolic stability in both microsomes and hepatocytes than did VU0467319. In both rat and dog <i>in vivo</i>, low doses proved to mirror the <i>in vitro</i> profile; however, at higher doses in 14-day exploratory toxicology studies, the amount of the same undesired metabolite derived from VU6045422 was equivalent to that produced from VU0467319. This unexpected IVIVC result, coupled with less than dose-proportional increases in exposure and no improvement in solubility, led to discontinuation of VU0467319/VU6045422 development.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":" ","pages":""},"PeriodicalIF":4.1000,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"ACS Chemical Neuroscience","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1021/acschemneuro.5c00119","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
Recently, we disclosed VU0467319, an M1 positive allosteric modulator (PAM) clinical candidate that had successfully completed a phase I single ascending dose clinical trial. Pharmacokinetic assessment revealed that, in humans upon increasing dose, a circulating, inactive metabolite constituted a major portion of the total drug-related area under the curve (AUC). One approach the team employed to reduce inactive metabolite formation in the back-up program was the kinetic isotope effect, replacing the metabolically labile C-H bonds with shorter, more stable C-D bonds. The C-D dipole afforded VU6045422, a more potent M1 PAM (human EC50 = 192 nM, 80% ACh Max) than its proteocongener VU0467319 (human EC50 = 492 nM, 71% ACh Max), and retained the desired profile of minimal M1 agonism. Overall, the profile of VU6045422 supported advancement, as did greater in vitro metabolic stability in both microsomes and hepatocytes than did VU0467319. In both rat and dog in vivo, low doses proved to mirror the in vitro profile; however, at higher doses in 14-day exploratory toxicology studies, the amount of the same undesired metabolite derived from VU6045422 was equivalent to that produced from VU0467319. This unexpected IVIVC result, coupled with less than dose-proportional increases in exposure and no improvement in solubility, led to discontinuation of VU0467319/VU6045422 development.
最近,我们披露了一种M1阳性变构调节剂(PAM)临床候选药物VU0467319,该药物已成功完成I期单次递增剂量临床试验。药代动力学评估显示,在人体中,随着剂量的增加,一种循环的、无活性的代谢物构成了总药物相关曲线下面积(AUC)的主要部分。在备用程序中,研究小组采用的一种减少无活性代谢物形成的方法是动力学同位素效应,用更短、更稳定的C-D键取代代谢不稳定的C-H键。C-D偶极子为VU6045422提供了比其蛋白同系物VU0467319(人EC50 = 492nm, ACh Max 71%)更有效的M1 PAM(人EC50 = 192nm, ACh Max 80%),并保留了所需的最小M1激动作用谱。总体而言,与VU0467319相比,VU6045422在微粒体和肝细胞中的体外代谢稳定性更高,支持了研究进展。在大鼠和狗体内,低剂量被证明反映了体外的情况;然而,在为期14天的探索性毒理学研究中,在更高剂量下,来自VU6045422的相同不希望的代谢物的数量与来自VU0467319的相同。这一意想不到的IVIVC结果,加上暴露量的增加低于剂量比例,且溶解度没有改善,导致VU0467319/VU6045422的开发停止。
期刊介绍:
ACS Chemical Neuroscience publishes high-quality research articles and reviews that showcase chemical, quantitative biological, biophysical and bioengineering approaches to the understanding of the nervous system and to the development of new treatments for neurological disorders. Research in the journal focuses on aspects of chemical neurobiology and bio-neurochemistry such as the following:
Neurotransmitters and receptors
Neuropharmaceuticals and therapeutics
Neural development—Plasticity, and degeneration
Chemical, physical, and computational methods in neuroscience
Neuronal diseases—basis, detection, and treatment
Mechanism of aging, learning, memory and behavior
Pain and sensory processing
Neurotoxins
Neuroscience-inspired bioengineering
Development of methods in chemical neurobiology
Neuroimaging agents and technologies
Animal models for central nervous system diseases
Behavioral research