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. Epub 2014 Sep 3.

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).

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Allosteric Regulation / drug effects
  • Animals
  • Central Nervous System / metabolism*
  • Drug Discovery*
  • Drug Evaluation, Preclinical
  • High-Throughput Screening Assays
  • Humans
  • Indazoles / chemistry
  • Indazoles / metabolism*
  • Indazoles / pharmacokinetics
  • Indazoles / pharmacology*
  • Male
  • Piperidines / chemistry
  • Piperidines / metabolism*
  • Piperidines / pharmacokinetics
  • Piperidines / pharmacology*
  • Rats
  • Receptor, Muscarinic M5 / chemistry*
  • Receptor, Muscarinic M5 / metabolism*
  • Substrate Specificity
  • Sulfonamides / chemistry
  • Sulfonamides / metabolism*
  • Sulfonamides / pharmacokinetics
  • Sulfonamides / pharmacology*

Substances

  • 1-((1H-Indazol-5-yl)sulfonyl)-N-ethyl-N-(2-(trifluoromethyl)benzyl)piperidine-4-carboxamide
  • Indazoles
  • Piperidines
  • Receptor, Muscarinic M5
  • Sulfonamides
  • piperidine