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)

Patrick R Gentry; 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

doi:10.1021/jm500995y

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)

Patrick R Gentry, 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

17 Citations (Scopus)

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).

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	https://doi.org/10.1021/jm500995y
Publication status	Published - 25 Sept 2014
Externally published	Yes

Keywords

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

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10.1021/jm500995y

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Gentry, P. R., Kokubo, M., Bridges, T. M., Noetzel, M. J., Cho, H. P., Lamsal, A., Smith, E., Chase, P., Hodder, P. S., Niswender, C. M., Daniels, J. S., Conn, P. J., Lindsley, C. W., & Wood, M. R. (2014). 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). Journal of Medicinal Chemistry, 57(18), 7804-10. https://doi.org/10.1021/jm500995y

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). / Gentry, Patrick R; Kokubo, Masaya; Bridges, Thomas M et al.

In: Journal of Medicinal Chemistry, Vol. 57, No. 18, 25.09.2014, p. 7804-10.

Research output: Contribution to journal › Journal article › Research › peer-review

Gentry, PR, Kokubo, M, Bridges, TM, Noetzel, MJ, Cho, HP, Lamsal, A, Smith, E, Chase, P, Hodder, PS, Niswender, CM, Daniels, JS, Conn, PJ, Lindsley, CW & Wood, MR 2014, '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)', Journal of Medicinal Chemistry, vol. 57, no. 18, pp. 7804-10. https://doi.org/10.1021/jm500995y

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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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T2 - 1-((1H-indazol-5-yl)sulfoneyl)-N-ethyl-N-(2-(trifluoromethyl)benzyl)piperidine-4-carboxamide (ML380)

AU - Gentry, Patrick R

AU - Kokubo, Masaya

AU - Bridges, Thomas M

AU - Noetzel, Meredith J

AU - Cho, Hyekyung P

AU - Lamsal, Atin

AU - Smith, Emery

AU - Chase, Peter

AU - Hodder, Peter S

AU - Niswender, Colleen M

AU - Daniels, J Scott

AU - Conn, P Jeffrey

AU - Lindsley, Craig W

AU - Wood, Michael R

PY - 2014/9/25

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AB - 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).

KW - Allosteric Regulation/drug effects

KW - Animals

KW - Central Nervous System/metabolism

KW - Drug Discovery

KW - Drug Evaluation, Preclinical

KW - High-Throughput Screening Assays

KW - Humans

KW - Indazoles/chemistry

KW - Male

KW - Piperidines/chemistry

KW - Rats

KW - Receptor, Muscarinic M5/chemistry

KW - Substrate Specificity

KW - Sulfonamides/chemistry

U2 - 10.1021/jm500995y

DO - 10.1021/jm500995y

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JO - Journal of Medicinal Chemistry

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