Development of a highly potent, novel M5positive allosteric modulator (PAM) demonstrating CNS exposure: 1-((1H-indazol-5-yl)sulfoneyl)-N-ethyl-N-(2-(trifluoromethyl)benzyl)piperidine-4-carboxamide (ML380)

Patrick R. Gentry; Masaya Kokubo; Thomas M. Bridges; Meredith J. Noetzel; Hyekyung P. Cho; Atin Lamsal; Emery Smith; Peter Chase; Peter S. Hodder; Colleen M. Niswender; J. Scott Daniels; P. Jeffrey Conn; Craig W. Lindsley; Michael R. Wood

Journal ArticleOPEN ACCESS

Development of a highly potent, novel M5positive allosteric modulator (PAM) demonstrating CNS exposure: 1-((1H-indazol-5-yl)sulfoneyl)-N-ethyl-N-(2-(trifluoromethyl)benzyl)piperidine-4-carboxamide (ML380)

Journal of Medicinal Chemistry (2014) 57(18) 7804-7810

DOI: 10.1021/jm500995y

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Abstract

A functional high throughput screen identified a novel chemotype for the positive allosteric modulation (PAM) of the muscarinic acetylcholine receptor (mAChR) subtype 5 (M5). Application of rapid analog, iterative parallel synthesis efficiently optimized M5potency to arrive at the most potent M5PAMs prepared to date and provided tool compound 8n (ML380) demonstrating modest CNS penetration (human M5EC50= 190 nM, rat M5EC50= 610 nM, brain to plasma ratio (Kp) of 0.36).

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Gentry, P. R., Kokubo, M., Bridges, T. M., Noetzel, M. J., Cho, H. P., Lamsal, A., … Wood, M. R. (2014). Development of a highly potent, novel M5positive allosteric modulator (PAM) demonstrating CNS exposure: 1-((1H-indazol-5-yl)sulfoneyl)-N-ethyl-N-(2-(trifluoromethyl)benzyl)piperidine-4-carboxamide (ML380). Journal of Medicinal Chemistry, 57(18), 7804–7810. https://doi.org/10.1021/jm500995y

Development of a highly potent, novel M5positive allosteric modulator (PAM) demonstrating CNS exposure: 1-((1H-indazol-5-yl)sulfoneyl)-N-ethyl-N-(2-(trifluoromethyl)benzyl)piperidine-4-carboxamide (ML380)

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