Development of a Highly Potent, Novel M(5) Positive Allosteric Modulator (PAM) Demonstrating CNS Exposure: 1-((1H-Indazol-5-yl)sulfoneyl)-N-ethyl-N-(2-(trifluoromethyl)benzyl)piperidine-4-carboxamide (ML380)

[Image: see text] A functional high throughput screen identified a novel chemotype for the positive allosteric modulation (PAM) of the muscarinic acetylcholine receptor (mAChR) subtype 5 (M(5)). Application of rapid analog, iterative parallel synthesis efficiently optimized M(5) potency to arrive at...

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Autores principales: Gentry, Patrick R., Kokubo, Masaya, Bridges, Thomas M., Noetzel, Meredith J., Cho, Hyekyung P., Lamsal, Atin, Smith, Emery, Chase, Peter, Hodder, Peter S., Niswender, Colleen M., Daniels, J. Scott, Conn, P. Jeffrey, Lindsley, Craig W., Wood, Michael R.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society 2014
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4175000/
https://www.ncbi.nlm.nih.gov/pubmed/25147929
http://dx.doi.org/10.1021/jm500995y
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author Gentry, Patrick R.
Kokubo, Masaya
Bridges, Thomas M.
Noetzel, Meredith J.
Cho, Hyekyung P.
Lamsal, Atin
Smith, Emery
Chase, Peter
Hodder, Peter S.
Niswender, Colleen M.
Daniels, J. Scott
Conn, P. Jeffrey
Lindsley, Craig W.
Wood, Michael R.
author_facet Gentry, Patrick R.
Kokubo, Masaya
Bridges, Thomas M.
Noetzel, Meredith J.
Cho, Hyekyung P.
Lamsal, Atin
Smith, Emery
Chase, Peter
Hodder, Peter S.
Niswender, Colleen M.
Daniels, J. Scott
Conn, P. Jeffrey
Lindsley, Craig W.
Wood, Michael R.
author_sort Gentry, Patrick R.
collection PubMed
description [Image: see text] A functional high throughput screen identified a novel chemotype for the positive allosteric modulation (PAM) of the muscarinic acetylcholine receptor (mAChR) subtype 5 (M(5)). Application of rapid analog, iterative parallel synthesis efficiently optimized M(5) potency to arrive at the most potent M(5) PAMs prepared to date and provided tool compound 8n (ML380) demonstrating modest CNS penetration (human M(5) EC(50) = 190 nM, rat M(5) EC(50) = 610 nM, brain to plasma ratio (K(p)) of 0.36).
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spelling pubmed-41750002015-08-22 Development of a Highly Potent, Novel M(5) Positive Allosteric Modulator (PAM) Demonstrating CNS Exposure: 1-((1H-Indazol-5-yl)sulfoneyl)-N-ethyl-N-(2-(trifluoromethyl)benzyl)piperidine-4-carboxamide (ML380) Gentry, Patrick R. Kokubo, Masaya Bridges, Thomas M. Noetzel, Meredith J. Cho, Hyekyung P. Lamsal, Atin Smith, Emery Chase, Peter Hodder, Peter S. Niswender, Colleen M. Daniels, J. Scott Conn, P. Jeffrey Lindsley, Craig W. Wood, Michael R. J Med Chem [Image: see text] A functional high throughput screen identified a novel chemotype for the positive allosteric modulation (PAM) of the muscarinic acetylcholine receptor (mAChR) subtype 5 (M(5)). Application of rapid analog, iterative parallel synthesis efficiently optimized M(5) potency to arrive at the most potent M(5) PAMs prepared to date and provided tool compound 8n (ML380) demonstrating modest CNS penetration (human M(5) EC(50) = 190 nM, rat M(5) EC(50) = 610 nM, brain to plasma ratio (K(p)) of 0.36). American Chemical Society 2014-08-22 2014-09-25 /pmc/articles/PMC4175000/ /pubmed/25147929 http://dx.doi.org/10.1021/jm500995y Text en Copyright © 2014 American Chemical Society Terms of Use (http://pubs.acs.org/page/policy/authorchoice_termsofuse.html)
spellingShingle Gentry, Patrick R.
Kokubo, Masaya
Bridges, Thomas M.
Noetzel, Meredith J.
Cho, Hyekyung P.
Lamsal, Atin
Smith, Emery
Chase, Peter
Hodder, Peter S.
Niswender, Colleen M.
Daniels, J. Scott
Conn, P. Jeffrey
Lindsley, Craig W.
Wood, Michael R.
Development of a Highly Potent, Novel M(5) Positive Allosteric Modulator (PAM) Demonstrating CNS Exposure: 1-((1H-Indazol-5-yl)sulfoneyl)-N-ethyl-N-(2-(trifluoromethyl)benzyl)piperidine-4-carboxamide (ML380)
title Development of a Highly Potent, Novel M(5) Positive Allosteric Modulator (PAM) Demonstrating CNS Exposure: 1-((1H-Indazol-5-yl)sulfoneyl)-N-ethyl-N-(2-(trifluoromethyl)benzyl)piperidine-4-carboxamide (ML380)
title_full Development of a Highly Potent, Novel M(5) Positive Allosteric Modulator (PAM) Demonstrating CNS Exposure: 1-((1H-Indazol-5-yl)sulfoneyl)-N-ethyl-N-(2-(trifluoromethyl)benzyl)piperidine-4-carboxamide (ML380)
title_fullStr Development of a Highly Potent, Novel M(5) Positive Allosteric Modulator (PAM) Demonstrating CNS Exposure: 1-((1H-Indazol-5-yl)sulfoneyl)-N-ethyl-N-(2-(trifluoromethyl)benzyl)piperidine-4-carboxamide (ML380)
title_full_unstemmed Development of a Highly Potent, Novel M(5) Positive Allosteric Modulator (PAM) Demonstrating CNS Exposure: 1-((1H-Indazol-5-yl)sulfoneyl)-N-ethyl-N-(2-(trifluoromethyl)benzyl)piperidine-4-carboxamide (ML380)
title_short Development of a Highly Potent, Novel M(5) Positive Allosteric Modulator (PAM) Demonstrating CNS Exposure: 1-((1H-Indazol-5-yl)sulfoneyl)-N-ethyl-N-(2-(trifluoromethyl)benzyl)piperidine-4-carboxamide (ML380)
title_sort development of a highly potent, novel m(5) positive allosteric modulator (pam) demonstrating cns exposure: 1-((1h-indazol-5-yl)sulfoneyl)-n-ethyl-n-(2-(trifluoromethyl)benzyl)piperidine-4-carboxamide (ml380)
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4175000/
https://www.ncbi.nlm.nih.gov/pubmed/25147929
http://dx.doi.org/10.1021/jm500995y
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