Discovery of the first M5-selective and CNS penetrant negative allosteric modulator (NAM) of a muscarinic acetylcholine receptor: (S)-9b-(4-chlorophenyl)-1-(3,4-difluorobenzoyl)-2,3-dihydro-1H-imidazo[2,1-a]isoindol-5(9bH)-one (ML375)

Patrick R Gentry; Masaya Kokubo; Thomas M Bridges; Nathan R Kett; Joel M Harp; Hyekyung P Cho; Emery Smith; Peter Chase; Peter S Hodder; Colleen M Niswender; J Scott Daniels; P Jeffrey Conn; Michael R Wood; Craig W Lindsley

doi:10.1021/jm4013246

Discovery of the first M5-selective and CNS penetrant negative allosteric modulator (NAM) of a muscarinic acetylcholine receptor: (S)-9b-(4-chlorophenyl)-1-(3,4-difluorobenzoyl)-2,3-dihydro-1H-imidazo[2,1-a]isoindol-5(9bH)-one (ML375)

Patrick R Gentry, Masaya Kokubo, Thomas M Bridges, Nathan R Kett, Joel M Harp, Hyekyung P Cho, Emery Smith, Peter Chase, Peter S Hodder, Colleen M Niswender, J Scott Daniels, P Jeffrey Conn, Michael R Wood, Craig W Lindsley

33 Citations (Scopus)

Abstract

A functional high throughput screen and subsequent multidimensional, iterative parallel synthesis effort identified the first muscarinic acetylcholine receptor (mAChR) negative allosteric modulator (NAM) selective for the M5 subtype. ML375 is a highly selective M5 NAM with submicromolar potency (human M5 IC50 = 300 nM, rat M5 IC50 = 790 nM, M1-M4 IC50 > 30 μM), excellent multispecies PK, high CNS penetration, and enantiospecific inhibition.

Original language	English
Journal	Journal of Medicinal Chemistry
Volume	56
Issue number	22
Pages (from-to)	9351-5
Number of pages	5
ISSN	0022-2623
DOIs	https://doi.org/10.1021/jm4013246
Publication status	Published - 27 Nov 2013
Externally published	Yes

Keywords

Allosteric Regulation/drug effects
Animals
Brain/drug effects
CHO Cells
Cricetinae
Cricetulus
Drug Discovery
Drug Evaluation, Preclinical
Humans
Imidazoles/chemistry
Indoles/chemistry
Male
Rats
Receptor, Muscarinic M5/chemistry
Structure-Activity Relationship
Substrate Specificity

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10.1021/jm4013246

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Gentry, P. R., Kokubo, M., Bridges, T. M., Kett, N. R., Harp, J. M., Cho, H. P., Smith, E., Chase, P., Hodder, P. S., Niswender, C. M., Daniels, J. S., Conn, P. J., Wood, M. R., & Lindsley, C. W. (2013). Discovery of the first M5-selective and CNS penetrant negative allosteric modulator (NAM) of a muscarinic acetylcholine receptor: (S)-9b-(4-chlorophenyl)-1-(3,4-difluorobenzoyl)-2,3-dihydro-1H-imidazo[2,1-a]isoindol-5(9bH)-one (ML375). Journal of Medicinal Chemistry, 56(22), 9351-5. https://doi.org/10.1021/jm4013246

Discovery of the first M5-selective and CNS penetrant negative allosteric modulator (NAM) of a muscarinic acetylcholine receptor: (S)-9b-(4-chlorophenyl)-1-(3,4-difluorobenzoyl)-2,3-dihydro-1H-imidazo[2,1-a]isoindol-5(9bH)-one (ML375). / Gentry, Patrick R; Kokubo, Masaya; Bridges, Thomas M et al.

In: Journal of Medicinal Chemistry, Vol. 56, No. 22, 27.11.2013, p. 9351-5.

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

Gentry, PR, Kokubo, M, Bridges, TM, Kett, NR, Harp, JM, Cho, HP, Smith, E, Chase, P, Hodder, PS, Niswender, CM, Daniels, JS, Conn, PJ, Wood, MR & Lindsley, CW 2013, 'Discovery of the first M5-selective and CNS penetrant negative allosteric modulator (NAM) of a muscarinic acetylcholine receptor: (S)-9b-(4-chlorophenyl)-1-(3,4-difluorobenzoyl)-2,3-dihydro-1H-imidazo[2,1-a]isoindol-5(9bH)-one (ML375)', Journal of Medicinal Chemistry, vol. 56, no. 22, pp. 9351-5. https://doi.org/10.1021/jm4013246

Gentry PR, Kokubo M, Bridges TM, Kett NR, Harp JM, Cho HP et al. Discovery of the first M5-selective and CNS penetrant negative allosteric modulator (NAM) of a muscarinic acetylcholine receptor: (S)-9b-(4-chlorophenyl)-1-(3,4-difluorobenzoyl)-2,3-dihydro-1H-imidazo[2,1-a]isoindol-5(9bH)-one (ML375). Journal of Medicinal Chemistry. 2013 Nov 27;56(22):9351-5. doi: 10.1021/jm4013246

Gentry, Patrick R ; Kokubo, Masaya ; Bridges, Thomas M et al. / Discovery of the first M5-selective and CNS penetrant negative allosteric modulator (NAM) of a muscarinic acetylcholine receptor: (S)-9b-(4-chlorophenyl)-1-(3,4-difluorobenzoyl)-2,3-dihydro-1H-imidazo[2,1-a]isoindol-5(9bH)-one (ML375). In: Journal of Medicinal Chemistry. 2013 ; Vol. 56, No. 22. pp. 9351-5.

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AU - Gentry, Patrick R

AU - Kokubo, Masaya

AU - Bridges, Thomas M

AU - Kett, Nathan R

AU - Harp, Joel M

AU - Cho, Hyekyung P

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AU - Hodder, Peter S

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KW - CHO Cells

KW - Cricetinae

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KW - Humans

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KW - Indoles/chemistry

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KW - Substrate Specificity

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