title: 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.
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.
authors.affiliation: 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.|Tennessee Valley Healthcare System, ∇Department of Chemistry, and ○Vanderbilt Kennedy Center, Vanderbilt University , Nashville, Tennessee 37232, United States.
authors.forename: Kellie D
authors.initials: KD
authors.lastname: Nance
authors.affiliation: 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.|Tennessee Valley Healthcare System, ∇Department of Chemistry, and ○Vanderbilt Kennedy Center, Vanderbilt University , Nashville, Tennessee 37232, United States.
authors.forename: Emily L
authors.initials: EL
authors.lastname: Days
authors.affiliation: 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.|Tennessee Valley Healthcare System, ∇Department of Chemistry, and ○Vanderbilt Kennedy Center, Vanderbilt University , Nashville, Tennessee 37232, United States.
authors.forename: C David
authors.initials: CD
authors.lastname: Weaver
authors.affiliation: 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.|Tennessee Valley Healthcare System, ∇Department of Chemistry, and ○Vanderbilt Kennedy Center, Vanderbilt University , Nashville, Tennessee 37232, United States.
authors.forename: Anastasia
authors.initials: A
authors.lastname: Coldren
authors.affiliation: 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.|Tennessee Valley Healthcare System, ∇Department of Chemistry, and ○Vanderbilt Kennedy Center, Vanderbilt University , Nashville, Tennessee 37232, United States.
authors.forename: Tiffany D
authors.initials: TD
authors.lastname: Farmer
authors.affiliation: 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.|Tennessee Valley Healthcare System, ∇Department of Chemistry, and ○Vanderbilt Kennedy Center, Vanderbilt University , Nashville, Tennessee 37232, United States.
authors.forename: Hyekyung P
authors.initials: HP
authors.lastname: Cho
authors.affiliation: 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.|Tennessee Valley Healthcare System, ∇Department of Chemistry, and ○Vanderbilt Kennedy Center, Vanderbilt University , Nashville, Tennessee 37232, United States.
authors.forename: Colleen M
authors.initials: CM
authors.lastname: Niswender
authors.affiliation: 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.|Tennessee Valley Healthcare System, ∇Department of Chemistry, and ○Vanderbilt Kennedy Center, Vanderbilt University , Nashville, Tennessee 37232, United States.
authors.forename: Anna L
authors.initials: AL
authors.lastname: Blobaum
authors.affiliation: 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.|Tennessee Valley Healthcare System, ∇Department of Chemistry, and ○Vanderbilt Kennedy Center, Vanderbilt University , Nashville, Tennessee 37232, United States.
authors.forename: Kevin D
authors.initials: KD
authors.lastname: Niswender
authors.affiliation: 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.|Tennessee Valley Healthcare System, ∇Department of Chemistry, and ○Vanderbilt Kennedy Center, Vanderbilt University , Nashville, Tennessee 37232, United States.
authors.forename: Craig W
authors.identifier: 0000-0003-0168-1445
authors.initials: CW
authors.lastname: Lindsley
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001786:Blood Glucose / Q000032:analysis / Q000378:metabolism; D002478:Cells, Cultured; D002490:Central Nervous System / Q000187:drug effects / Q000378:metabolism; D000067757:Glucagon-Like Peptide-1 Receptor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D054879:Halogenation; D006801:Humans; D007328:Insulin / Q000097:blood / Q000378:metabolism; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism; D008297:Male; D011743:Pyrimidines / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D017207:Rats, Sprague-Dawley
chemical_list: D001786:Blood Glucose; D000067757:Glucagon-Like Peptide-1 Receptor; D007328:Insulin; D011743:Pyrimidines