Discovery and preclinical development of AR453588 as an anti-diabetic glucokinase activator.
Animals
Binding Sites
Blood Glucose
/ analysis
Crystallography, X-Ray
Diabetes Mellitus, Experimental
/ drug therapy
Drug Design
Drug Evaluation, Preclinical
Enzyme Activators
/ chemistry
Glucokinase
/ chemistry
Glucose Tolerance Test
Hypoglycemic Agents
/ chemistry
Kinetics
Mice
Mice, Inbred C57BL
Molecular Dynamics Simulation
Structure-Activity Relationship
Thiadiazoles
/ chemistry
Diabetes
Glucokinase
Glucokinase activator
OGTT
S(0.5)
Structure-aided design
Structure-based design
Type II diabetes
V(max)
ob/ob mouse
Journal
Bioorganic & medicinal chemistry
ISSN: 1464-3391
Titre abrégé: Bioorg Med Chem
Pays: England
ID NLM: 9413298
Informations de publication
Date de publication:
01 01 2020
01 01 2020
Historique:
received:
19
06
2019
revised:
14
11
2019
accepted:
20
11
2019
pubmed:
11
12
2019
medline:
21
1
2021
entrez:
11
12
2019
Statut:
ppublish
Résumé
Glucose flux through glucokinase (GK) controls insulin release from the pancreas in response to high levels of glucose. Flux through GK is also responsible for reducing hepatic glucose output. Since many individuals with type 2 diabetes appear to have an inadequacy or defect in one or both of these processes, identifying compounds that can activate GK could provide a therapeutic benefit. Herein we report the further structure activity studies of a novel series of glucokinase activators (GKA). These studies led to the identification of pyridine 72 as a potent GKA that lowered post-prandial glucose in normal C57BL/6J mice, and after 14d dosing in ob/ob mice.
Identifiants
pubmed: 31818630
pii: S0968-0896(19)31029-6
doi: 10.1016/j.bmc.2019.115232
pii:
doi:
Substances chimiques
Blood Glucose
0
Enzyme Activators
0
Hypoglycemic Agents
0
Thiadiazoles
0
Glucokinase
EC 2.7.1.2
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
115232Informations de copyright
Copyright © 2019 Elsevier Ltd. All rights reserved.