title: Synthetic small molecule GLP-1 secretagogues prepared by means of a three-component indole annulation strategy.
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.
authors.affiliation: Department of Medicine, State University of New York (SUNY), Upstate Medical University, Syracuse, New York, USA.
authors.forename: Oleg G
authors.initials: OG
authors.lastname: Chepurny
authors.affiliation: Department of Medicine, State University of New York (SUNY), Upstate Medical University, Syracuse, New York, USA.
authors.forename: Colin A
authors.initials: CA
authors.lastname: Leech
authors.affiliation: Department of Chemistry, Dartmouth College, Hanover, New Hampshire, USA.
authors.forename: Martin
authors.initials: M
authors.lastname: Tomanik
authors.affiliation: Department of Chemistry, Dartmouth College, Hanover, New Hampshire, USA.
authors.forename: Maria C
authors.initials: MC
authors.lastname: DiPoto
authors.affiliation: Department of Chemistry, Dartmouth College, Hanover, New Hampshire, USA.
authors.forename: Hui
authors.initials: H
authors.lastname: Li
authors.affiliation: Department of Chemistry, Dartmouth College, Hanover, New Hampshire, USA.
authors.forename: Xinping
authors.initials: X
authors.lastname: Han
authors.affiliation: Department of Surgery, State University of New York (SUNY), Upstate Medical University, Syracuse, New York, USA.
authors.forename: Qinghe
authors.initials: Q
authors.lastname: Meng
authors.affiliation: Department of Surgery, State University of New York (SUNY), Upstate Medical University, Syracuse, New York, USA.
authors.forename: Robert N
authors.initials: RN
authors.lastname: Cooney
authors.affiliation: Department of Chemistry, Dartmouth College, Hanover, New Hampshire, USA.
authors.forename: Jimmy
authors.initials: J
authors.lastname: Wu
authors.affiliation: Department of Medicine, State University of New York (SUNY), Upstate Medical University, Syracuse, New York, USA.|Department of Pharmacology, State University of New York (SUNY), Upstate Medical University, Syracuse, New York, USA.
authors.forename: George G
authors.initials: GG
authors.lastname: Holz
mesh_terms: D000818:Animals; D020013:Calcium Signaling / Q000187:drug effects; D004353:Drug Evaluation, Preclinical; D019858:Enteroendocrine Cells / Q000187:drug effects / Q000378:metabolism; D052216:Glucagon-Like Peptide 1 / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis* / Q000494:pharmacology; D051379:Mice; D013237:Stereoisomerism; D000074025:TRPA1 Cation Channel / Q000819:agonists
chemical_list: D007211:Indoles; D000074025:TRPA1 Cation Channel; D052216:Glucagon-Like Peptide 1