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 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
J Med Chem. 2014 57 (23): 10192-7

PMID: 25423411 · PMCID: PMC4266362 · DOI:10.1021/jm501375c

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.

MeSH Terms (22)

Allosteric Regulation Animals Catalepsy Central Nervous System Agents Drug Synergism Exenatide Glucagon-Like Peptide-1 Receptor Glucagon-Like Peptide 1 Haloperidol High-Throughput Screening Assays Indoles Insulin Insulin Secretion Islets of Langerhans Male Mice, Inbred C57BL Microsomes, Liver Peptides Pyrrolidines Receptors, Glucagon Structure-Activity Relationship Venoms

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