ArticleJournal of medicinal chemistry2014
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).
Article in Journal of medicinal chemistry, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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Who cites it
19 citing papers in PubMed.
- Cryo-EM reveals an extrahelical allosteric binding site at the MNature communications · 2025Article
- Repositioning VU-0365114 as a novel microtubule-destabilizing agent for treating cancer and overcoming drug resistance.Molecular oncology · 2024Article
- Article
- Multitargeting nature of muscarinic orthosteric agonists and antagonists.Frontiers in physiology · 2022Review
- Identification of a Novel Allosteric Site at the MACS chemical neuroscience · 2021Article
- Classification models and SAR analysis on CysLT1 receptor antagonists using machine learning algorithms.Molecular diversity · 2021Article
- Acute Negative Allosteric Modulation of MACS chemical neuroscience · 2019Article
- Structure-Activity Relationships of Pan-GαACS chemical neuroscience · 2018Article
- Discovery and Optimization of Potent and CNS Penetrant MACS chemical neuroscience · 2018Article
- Muscarinic MNeuropsychopharmacology : official publication of the American College of Neuropsychopharmacology · 2018Article
- Structure-based discovery of selective positive allosteric modulators of antagonists for the MProceedings of the National Academy of Sciences of the United States of America · 2018Article
- Discovery and optimization of 3-(4-aryl/heteroarylsulfonyl)piperazin-1-yl)-6-(piperidin-1-yl)pyridazines as novel, CNS penetrant pan-muscarinic antagonists.Bioorganic & medicinal chemistry letters · 2017Article
- Synthesis and evaluation of 4,6-disubstituted pyrimidines as CNS penetrant pan-muscarinic antagonists with a novel chemotype.Bioorganic & medicinal chemistry letters · 2017Article
- Continued optimization of the MBioorganic & medicinal chemistry letters · 2017Article
- Ligand-based virtual screen for the discovery of novel M5 inhibitor chemotypes.Bioorganic & medicinal chemistry letters · 2016Article
- Lead optimization of the VU0486321 series of mGlu1 PAMs. Part 3. Engineering plasma stability by discovery and optimization of isoindolinone analogs.Bioorganic & medicinal chemistry letters · 2016Article
- Lead optimization of the VU0486321 series of mGlu(1) PAMs. Part 2: SAR of alternative 3-methyl heterocycles and progress towards an in vivo tool.Bioorganic & medicinal chemistry letters · 2016Article
- Lead optimization of the VU0486321 series of mGlu1 PAMs. Part 1: SAR of modifications to the central aryl core.Bioorganic & medicinal chemistry letters · 2015Article
- Further optimization of the M5 NAM MLPCN probe ML375: tactics and challenges.Bioorganic & medicinal chemistry letters · 2015Article
Corrections and comments
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Authors and funding
14 authors.
Funding
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).
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.