2. Academic Validation
  3. Synthetic small molecule GLP-1 secretagogues prepared by means of a three-component indole annulation strategy

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

  • Sci Rep. 2016 Jun 29:6:28934. doi: 10.1038/srep28934.
Oleg G Chepurny 1,  Colin A Leech 1,  Martin Tomanik 2,  Maria C DiPoto 2,  Hui Li 2,  Xinping Han 2,  Qinghe Meng 3,  Robert N Cooney 3,  Jimmy Wu 2,  George G Holz 1 4
Affiliations

Affiliations

  • 1 Department of Medicine, State University of New York (SUNY), Upstate Medical University, Syracuse, New York, USA.
  • 2 Department of Chemistry, Dartmouth College, Hanover, New Hampshire, USA.
  • 3 Department of Surgery, State University of New York (SUNY), Upstate Medical University, Syracuse, New York, USA.
  • 4 Department of Pharmacology, State University of New York (SUNY), Upstate Medical University, Syracuse, New York, USA.
PMID: 27352904 DOI: 10.1038/srep28934
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 CA(2+) 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.

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