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 journal › Journal article › Research › peer-review
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 language | English |
|---|---|
| Journal | Journal of Medicinal Chemistry |
| Volume | 57 |
| Issue number | 18 |
| Pages (from-to) | 7804-10 |
| Number of pages | 7 |
| ISSN | 0022-2623 |
| DOIs | |
| Publication status | Published - 25 Sep 2014 |
| Externally published | Yes |
- 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
Research areas
ID: 213599564