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 journalJournal articleResearchpeer-review

Standard

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; 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.

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

Research output: Contribution to journalJournal articleResearchpeer-review

Harvard

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

APA

Gentry, P. R., Kokubo, M., Bridges, T. M., Noetzel, M. J., Cho, H. P., Lamsal, A., ... 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

Vancouver

Gentry PR, Kokubo M, Bridges TM, Noetzel MJ, Cho HP, Lamsal A et al. 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. 2014 Sep 25;57(18):7804-10. https://doi.org/10.1021/jm500995y

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. / 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). In: Journal of Medicinal Chemistry. 2014 ; Vol. 57, No. 18. pp. 7804-10.

Bibtex

@article{7b2b0da79c3049e3a256c9ec62b2e9c4,
title = "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)",
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).",
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",
author = "Gentry, {Patrick R} and Masaya Kokubo and Bridges, {Thomas M} and Noetzel, {Meredith J} and Cho, {Hyekyung P} and Atin Lamsal and Emery Smith and Peter Chase and Hodder, {Peter S} and Niswender, {Colleen M} and Daniels, {J Scott} and Conn, {P Jeffrey} and Lindsley, {Craig W} and Wood, {Michael R}",
year = "2014",
month = "9",
day = "25",
doi = "10.1021/jm500995y",
language = "English",
volume = "57",
pages = "7804--10",
journal = "Journal of Medicinal Chemistry",
issn = "0022-2623",
publisher = "American Chemical Society",
number = "18",

}

RIS

TY - JOUR

T1 - Development of a highly potent, novel M5 positive allosteric modulator (PAM) demonstrating CNS exposure

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

Y1 - 2014/9/25

N2 - 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).

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

M3 - Journal article

VL - 57

SP - 7804

EP - 7810

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

IS - 18

ER -

ID: 213599564