Discovery of (S)-2-Cyclopentyl-N-((1-isopropylpyrrolidin2-yl)-9-methyl-1-oxo-29-dihydro-1H-pyrrido34-bindole-4-carboxamide(VU0453379): A Novel CNS Penetrant Glucagon-Like Peptide 1 Receptor(GLP-1R) Positive Allosteric Modulator (PAM)

摘要

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.