Synthetic small molecule GLP-1 secretagogues prepared by means of a three-component indole annulation strategy

Oleg G. Chepurny, Colin A. Leech, Martin Tomanik, Maria C. Dipoto, Hui Li, Xinping Han, Qinghe Meng, Robert N. Cooney, Jimmy Wu, George G. Holz

Research output: Contribution to journalArticlepeer-review

Abstract

Rational assembly of small molecule libraries for purposes of drug discovery requires an efficient approach in which the synthesis of bioactive compounds is enabled so that numerous structurally related compounds of a similar basic formulation can be derived. Here, we describe (4+3) and (3+2) indole annulation strategies that quickly generate complex indole heterocycle libraries that contain novel cyclohepta-and cyclopenta[b]indoles, respectively. Screening of one such library comprised of these indoles identifies JWU-A021 to be an especially potent stimulator of glucagon-like peptide-1 (GLP-1) secretion in vitro. Surprisingly, JWU-A021 is also a potent stimulator of Ca2+ influx through TRPA1 cation channels (EC50 ca. 200 nM), thereby explaining its ability to stimulate GLP-1 release. Of additional importance, the available evidence indicates that JWU-A021 is one of the most potent non-electrophilic TRPA-1 channel agonists yet to be reported in the literature.

Original languageEnglish (US)
Article number28934
JournalScientific reports
Volume6
DOIs
StatePublished - Jun 29 2016

ASJC Scopus subject areas

  • General

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