2. Academic Validation
  3. Development of a highly potent, novel M5 positive allosteric modulator (PAM) demonstrating CNS exposure: 1-((1H-indazol-5-yl)sulfoneyl)-N-ethyl-N-(2-(trifluoromethyl)benzyl)piperidine-4-carboxamide (ML380)

Development of a highly potent, novel M5 positive allosteric modulator (PAM) demonstrating CNS exposure: 1-((1H-indazol-5-yl)sulfoneyl)-N-ethyl-N-(2-(trifluoromethyl)benzyl)piperidine-4-carboxamide (ML380)

  • J Med Chem. 2014 Sep 25;57(18):7804-10. doi: 10.1021/jm500995y.
Patrick R Gentry 1,  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
Affiliations

Affiliation

  • 1 Department of Pharmacology, ‡Vanderbilt Center for Neuroscience Drug Discovery, and §Vanderbilt Specialized Chemistry Center for Accelerated Probe Development (MLPCN), Vanderbilt University Medical Center , Nashville, Tennessee 37232, United States.
PMID: 25147929 DOI: 10.1021/jm500995y
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 M5 potency to arrive at the most potent M5 PAMs prepared to date and provided tool compound 8n (ML380) demonstrating modest CNS penetration (human M5 EC50 = 190 nM, rat M5 EC50 = 610 nM, brain to plasma ratio (Kp) of 0.36).

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