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) | Zendy

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

Open Access

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)

Author(s) -

Lindsey C. Morris,

Kellie D. Nance,

Patrick R. Gentry,

Emily 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

Publication year - 2014

Publication title -

journal of medicinal chemistry

Language(s) - English

Resource type - Journals

SCImago Journal Rank - 2.01

H-Index - 261

eISSN - 1520-4804

pISSN - 0022-2623

DOI - 10.1021/jm501375c

Subject(s) - chemistry , exenatide , haloperidol , allosteric modulator , endogeny , allosteric regulation , catalepsy , pancreatic islets , insulin , pharmacology , stereochemistry , islet , biochemistry , receptor , endocrinology , diabetes mellitus , type 2 diabetes , medicine , dopamine

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.

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