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

  • J Med Chem. 2017 Feb 23;60(4):1611-1616. doi: 10.1021/acs.jmedchem.6b01706.
Kellie D Nance  1  2 ,  Emily L Days  1  2 ,  C David Weaver  1  2 ,  Anastasia Coldren  1  2 ,  Tiffany D Farmer  1  2 ,  Hyekyung P Cho  1  2 ,  Colleen M Niswender  1  2 ,  Anna L Blobaum  1  2 ,  Kevin D Niswender  1  2 ,  Craig W Lindsley  1  2
Affiliations
  • 1. Department of Medicine, Division of Diabetes, Endocrinology and Metabolism, ‡Department of Pharmacology, §Vanderbilt Center for Neuroscience Drug Discovery, ∥Vanderbilt Institute of Chemical Biology, and ⊥Vanderbilt Diabetes Center, Vanderbilt University School of Medicine , Nashville, Tennessee 37232, United States.
  • 2. Tennessee Valley Healthcare System, ∇Department of Chemistry, and ○Vanderbilt Kennedy Center, Vanderbilt University , Nashville, Tennessee 37232, United States.
PMID: 28103022 DOI: 10.1021/acs.jmedchem.6b01706
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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