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)

Research output: Contribution to journalJournal articleResearchpeer-review

  • Lindsey C Morris
  • Kellie D Nance
  • Gentry, Patrick Ryan
  • 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

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 languageEnglish
JournalJournal of Medicinal Chemistry
Volume57
Issue number23
Pages (from-to)10192-7
Number of pages6
ISSN0022-2623
DOIs
Publication statusPublished - 11 Dec 2014
Externally publishedYes

    Research areas

  • 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

ID: 213599458