@article{7b2b0da79c3049e3a256c9ec62b2e9c4,
title = "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)",
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). ",
keywords = "Allosteric Regulation/drug effects, Animals, Central Nervous System/metabolism, Drug Discovery, Drug Evaluation, Preclinical, High-Throughput Screening Assays, Humans, Indazoles/chemistry, Male, Piperidines/chemistry, Rats, Receptor, Muscarinic M5/chemistry, Substrate Specificity, Sulfonamides/chemistry",
author = "Gentry, {Patrick R} and Masaya Kokubo and Bridges, {Thomas M} and Noetzel, {Meredith J} and Cho, {Hyekyung P} and Atin Lamsal and Emery Smith and Peter Chase and Hodder, {Peter S} and Niswender, {Colleen M} and Daniels, {J Scott} and Conn, {P Jeffrey} and Lindsley, {Craig W} and Wood, {Michael R}",
year = "2014",
month = sep,
day = "25",
doi = "10.1021/jm500995y",
language = "English",
volume = "57",
pages = "7804--10",
journal = "Journal of Medicinal Chemistry",
issn = "0022-2623",
publisher = "American Chemical Society",
number = "18",
}