2. Academic Validation
  3. 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)

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)

  • J Med Chem. 2014 Dec 11;57(23):10192-7. doi: 10.1021/jm501375c.
Lindsey C Morris 1,  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
Affiliations

Affiliation

  • 1 Department of Medicine, Division of Diabetes, Endocrinology and Metabolism, ‡Department of Pharmacology, §Vanderbilt Center for Neuroscience Drug Discovery, ∥Vanderbilt Institute of Chemical Biology, Vanderbilt University School of Medicine , Nashville, Tennessee 37232, United States .
PMID: 25423411 DOI: 10.1021/jm501375c
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.

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