Discovery of (S)-2-cyclopentyl-N-((1-isopropylpyrrolidin2-yl)-9-methyl-1-oxo-2,9-dihydro-1H-pyrrido[3,4-b]indole-4-carboxamide (VU0453379): a novel, CNS penetrant glucagon-like peptide 1 receptor (GLP-1R) positive allosteric modulator (PAM)

Lindsey C Morris; Kellie D Nance; Patrick R Gentry; Emily L Days; C David Weaver; Colleen M Niswender; Analisa D Thompson; Carrie K Jones; Chuck W Locuson; Ryan D Morrison; J Scott Daniels; Kevin D Niswender; Craig W Lindsley

doi:10.1021/jm501375c

Discovery of (S)-2-cyclopentyl-N-((1-isopropylpyrrolidin2-yl)-9-methyl-1-oxo-2,9-dihydro-1H-pyrrido[3,4-b]indole-4-carboxamide (VU0453379): a novel, CNS penetrant glucagon-like peptide 1 receptor (GLP-1R) positive allosteric modulator (PAM)

Lindsey C Morris, Kellie D Nance, Patrick R Gentry, Emily L Days, C David Weaver, Colleen M Niswender, Analisa D Thompson, Carrie K Jones, Chuck W Locuson, Ryan D Morrison, J Scott Daniels, Kevin D Niswender, Craig W Lindsley

28 Citations (Scopus)

Abstract

A duplexed, functional multiaddition high throughput screen and subsequent iterative parallel synthesis effort identified the first highly selective and CNS penetrant glucagon-like peptide-1R (GLP-1R) positive allosteric modulator (PAM). PAM (S)-9b potentiated low-dose exenatide to augment insulin secretion in primary mouse pancreatic islets, and (S)-9b alone was effective in potentiating endogenous GLP-1R to reverse haloperidol-induced catalepsy.

Original language	English
Journal	Journal of Medicinal Chemistry
Volume	57
Issue number	23
Pages (from-to)	10192-7
Number of pages	6
ISSN	0022-2623
DOIs	https://doi.org/10.1021/jm501375c
Publication status	Published - 11 Dec 2014
Externally published	Yes

Keywords

Allosteric Regulation/drug effects
Animals
Catalepsy/chemically induced
Central Nervous System Agents/therapeutic use
Drug Synergism
Exenatide
Glucagon-Like Peptide 1/pharmacology
Glucagon-Like Peptide-1 Receptor
Haloperidol
High-Throughput Screening Assays
Indoles/chemical synthesis
Insulin/metabolism
Insulin Secretion
Islets of Langerhans/drug effects
Male
Mice, Inbred C57BL
Microsomes, Liver/metabolism
Peptides/pharmacology
Pyrrolidines/chemical synthesis
Receptors, Glucagon/drug effects
Structure-Activity Relationship
Venoms/pharmacology

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Morris, L. C., Nance, K. D., Gentry, P. R., Days, E. L., Weaver, C. D., Niswender, C. M., Thompson, A. D., Jones, C. K., Locuson, C. W., Morrison, R. D., Daniels, J. S., Niswender, K. D., & Lindsley, C. W. (2014). Discovery of (S)-2-cyclopentyl-N-((1-isopropylpyrrolidin2-yl)-9-methyl-1-oxo-2,9-dihydro-1H-pyrrido[3,4-b]indole-4-carboxamide (VU0453379): a novel, CNS penetrant glucagon-like peptide 1 receptor (GLP-1R) positive allosteric modulator (PAM). Journal of Medicinal Chemistry, 57(23), 10192-7. https://doi.org/10.1021/jm501375c

Discovery of (S)-2-cyclopentyl-N-((1-isopropylpyrrolidin2-yl)-9-methyl-1-oxo-2,9-dihydro-1H-pyrrido[3,4-b]indole-4-carboxamide (VU0453379) : a novel, CNS penetrant glucagon-like peptide 1 receptor (GLP-1R) positive allosteric modulator (PAM). / Morris, Lindsey C; Nance, Kellie D; Gentry, Patrick R et al.

In: Journal of Medicinal Chemistry, Vol. 57, No. 23, 11.12.2014, p. 10192-7.

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

Morris, LC, Nance, KD, Gentry, PR, Days, EL, Weaver, CD, Niswender, CM, Thompson, AD, Jones, CK, Locuson, CW, Morrison, RD, Daniels, JS, Niswender, KD & Lindsley, CW 2014, 'Discovery of (S)-2-cyclopentyl-N-((1-isopropylpyrrolidin2-yl)-9-methyl-1-oxo-2,9-dihydro-1H-pyrrido[3,4-b]indole-4-carboxamide (VU0453379): a novel, CNS penetrant glucagon-like peptide 1 receptor (GLP-1R) positive allosteric modulator (PAM)', Journal of Medicinal Chemistry, vol. 57, no. 23, pp. 10192-7. https://doi.org/10.1021/jm501375c

Morris LC, Nance KD, Gentry PR, Days EL, Weaver CD, Niswender CM et al. Discovery of (S)-2-cyclopentyl-N-((1-isopropylpyrrolidin2-yl)-9-methyl-1-oxo-2,9-dihydro-1H-pyrrido[3,4-b]indole-4-carboxamide (VU0453379): a novel, CNS penetrant glucagon-like peptide 1 receptor (GLP-1R) positive allosteric modulator (PAM). Journal of Medicinal Chemistry. 2014 Dec 11;57(23):10192-7. doi: 10.1021/jm501375c

Morris, Lindsey C ; Nance, Kellie D ; Gentry, Patrick R et al. / Discovery of (S)-2-cyclopentyl-N-((1-isopropylpyrrolidin2-yl)-9-methyl-1-oxo-2,9-dihydro-1H-pyrrido[3,4-b]indole-4-carboxamide (VU0453379) : a novel, CNS penetrant glucagon-like peptide 1 receptor (GLP-1R) positive allosteric modulator (PAM). In: Journal of Medicinal Chemistry. 2014 ; Vol. 57, No. 23. pp. 10192-7.

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title = "Discovery of (S)-2-cyclopentyl-N-((1-isopropylpyrrolidin2-yl)-9-methyl-1-oxo-2,9-dihydro-1H-pyrrido[3,4-b]indole-4-carboxamide (VU0453379): a novel, CNS penetrant glucagon-like peptide 1 receptor (GLP-1R) positive allosteric modulator (PAM)",

abstract = "A duplexed, functional multiaddition high throughput screen and subsequent iterative parallel synthesis effort identified the first highly selective and CNS penetrant glucagon-like peptide-1R (GLP-1R) positive allosteric modulator (PAM). PAM (S)-9b potentiated low-dose exenatide to augment insulin secretion in primary mouse pancreatic islets, and (S)-9b alone was effective in potentiating endogenous GLP-1R to reverse haloperidol-induced catalepsy. ",

keywords = "Allosteric Regulation/drug effects, Animals, Catalepsy/chemically induced, Central Nervous System Agents/therapeutic use, Drug Synergism, Exenatide, Glucagon-Like Peptide 1/pharmacology, Glucagon-Like Peptide-1 Receptor, Haloperidol, High-Throughput Screening Assays, Indoles/chemical synthesis, Insulin/metabolism, Insulin Secretion, Islets of Langerhans/drug effects, Male, Mice, Inbred C57BL, Microsomes, Liver/metabolism, Peptides/pharmacology, Pyrrolidines/chemical synthesis, Receptors, Glucagon/drug effects, Structure-Activity Relationship, Venoms/pharmacology",

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AU - Niswender, Kevin D

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