Optimization of a novel series of potent and orally bioavailable GPR119 agonists

[Display omitted] We describe the discovery and optimization of a novel series of furo[3,2-d]pyrimidines as G protein-coupled receptor 119 agonists. Agonistic activity of 4 (EC50=129nM) was improved by replacing the intramolecular hydrogen bond between the fluorine atom and the aniline hydrogen in t...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2017-08, Vol.27 (15), p.3249-3253
Main Authors: Koshizawa, Tomoaki, Morimoto, Toshiharu, Watanabe, Gen, Watanabe, Toshiaki, Yamasaki, Nao, Sawada, Yoshikazu, Fukuda, Tomoaki, Okuda, Ayumu, Shibuya, Kimiyuki, Ohgiya, Tadaaki
Format: Article
Language:English
Subjects:
Administration, Oral
Animals
Blood Glucose - analysis
Blood Glucose - metabolism
Diabetes Mellitus, Type 2 - drug therapy
Diabetes Mellitus, Type 2 - metabolism
Furo[3,2-d]pyrimidine
Glucose Tolerance Test
GPR119 agonists
Humans
Hypoglycemic Agents - administration & dosage
Hypoglycemic Agents - chemistry
Hypoglycemic Agents - pharmacokinetics
Hypoglycemic Agents - pharmacology
Intramolecular hydrogen bond
Mice, Inbred C57BL
Pyrimidines - administration & dosage
Pyrimidines - chemistry
Pyrimidines - pharmacokinetics
Pyrimidines - pharmacology
Receptors, G-Protein-Coupled - agonists
Receptors, G-Protein-Coupled - metabolism
Restricted conformation
Structure-Activity Relationship
Type 2 diabetes mellitus
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Summary:[Display omitted] We describe the discovery and optimization of a novel series of furo[3,2-d]pyrimidines as G protein-coupled receptor 119 agonists. Agonistic activity of 4 (EC50=129nM) was improved by replacing the intramolecular hydrogen bond between the fluorine atom and the aniline hydrogen in the head moiety with a covalent C-C bond to enhance conformational restriction, which consequently gave a lead compound 12 (EC50=53nM). Optimized compound 26, which was identified by the further optimization of 12, exhibited potent activity (EC50=42nM) with improved clearance in liver microsomes and induced a 33% reduction in blood glucose area under the curve at a dose of 10mg/kg in an oral glucose tolerance test in C57BL/6N mice.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2017.06.034