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.

Nance KD, Days EL, Weaver CD, Coldren A, Farmer TD, Cho HP, Niswender CM, Blobaum AL, Niswender KD, Lindsley CW
J Med Chem. 2017 60 (4): 1611-1616

PMID: 28103022 · DOI:10.1021/acs.jmedchem.6b01706

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.

MeSH Terms (13)

Administration, Oral Animals Blood Glucose Cells, Cultured Central Nervous System Glucagon-Like Peptide-1 Receptor Halogenation Humans Insulin Islets of Langerhans Male Pyrimidines Rats, Sprague-Dawley

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