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).

Gentry PR, Kokubo M, Bridges TM, Noetzel MJ, Cho HP, Lamsal A, Smith E, Chase P, Hodder PS, Niswender CM, Daniels JS, Conn PJ, Lindsley CW, Wood MR
J Med Chem. 2014 57 (18): 7804-10

PMID: 25147929 · PMCID: PMC4175000 · DOI:10.1021/jm500995y

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).

MeSH Terms (14)

Allosteric Regulation Animals Central Nervous System Drug Discovery Drug Evaluation, Preclinical High-Throughput Screening Assays Humans Indazoles Male Piperidines Rats Receptor, Muscarinic M5 Substrate Specificity Sulfonamides

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