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

Kellie D Nance; Emily L Days; C David Weaver; Anastasia Coldren; Tiffany D Farmer; Hyekyung P Cho; Colleen M Niswender; Anna L Blobaum; Kevin D Niswender; Craig W Lindsley

doi:10.1021/acs.jmedchem.6b01706

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. Epub 2017 Feb 3.

Authors

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Administration, Oral
Animals
Blood Glucose / analysis
Blood Glucose / metabolism
Cells, Cultured
Central Nervous System / drug effects
Central Nervous System / metabolism
Glucagon-Like Peptide-1 Receptor / antagonists & inhibitors*
Glucagon-Like Peptide-1 Receptor / metabolism
Halogenation
Humans
Insulin / blood
Insulin / metabolism
Islets of Langerhans / drug effects
Islets of Langerhans / metabolism
Male
Pyrimidines / administration & dosage
Pyrimidines / chemistry*
Pyrimidines / pharmacokinetics
Pyrimidines / pharmacology*
Rats, Sprague-Dawley

Substances

Blood Glucose
Glucagon-Like Peptide-1 Receptor
Insulin
Pyrimidines