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)

Research output: Contribution to journalJournal articleResearchpeer-review

  • Gentry, Patrick Ryan
  • 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

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).

Original languageEnglish
JournalJournal of Medicinal Chemistry
Issue number18
Pages (from-to)7804-10
Number of pages7
Publication statusPublished - 25 Sep 2014
Externally publishedYes

    Research areas

  • 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

ID: 213599564