☆ 4.7 Article

Discovery of a Novel Series of Orally Bioavailable and CNS Penetrant Glucagon-like Peptide-1 Receptor (GLP-1R) Noncompetitive Antagonists Based on a 1,3-Disubstituted-7-aryl-5,5-bis(trifluoromethyl)-5,8-dihydropyrimido[4,5-d]pyrimidine-2,4(1H,3H)-dione Core

JOURNAL OF MEDICINAL CHEMISTRY (2017)

Journal

JOURNAL OF MEDICINAL CHEMISTRY

Volume 60, Issue 4, Pages 1611-1616

Publisher

AMER CHEMICAL SOC

DOI: 10.1021/acs.jmedchem.6b01706

Keywords

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Categories

Chemistry, Medicinal

Funding

NIH [GM06232]
Warren Family and Foundation
American Diabetes Association research award
Vanderbilt Diabetes and Research Training Center Pilot and Feasibility award
Vanderbilt Diabetes and Research Training Center [DK020593]

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Abstract

A duplexed, functional multiaddition high throughput screen and subsequent optimization effort identified the first orally bioavailable and CNS penetrant glucagon like peptide-1 receptor (GLP-1R) noncompetitive antagonist. Antagonist 5d not only blocked exendin-4-stimulated insulin release in islets but also lowered insulin levels while increasing blood glucose in vivo.

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