Discovery of liver selective non-steroidal glucocorticoid receptor antagonist as novel antidiabetic agents

Series of benzyl-phenoxybenzyl amino-phenyl acid derivatives are reported as non-steroidal GR antagonist. The lead compound 8g exhibited significant oral antidiabetic and antihyperlipidemic effects (in vivo), along with liver selectivity. Series of benzyl-phenoxybenzyl amino-phenyl acid derivatives...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2012-09, Vol.22 (18), p.5857-5862
Main Authors: Shah, Kiran, Patel, Dipam, Jadav, Pradip, Sheikh, Mubeen, Sairam, Kalapatapu V.V.M., Joharapurkar, Amit, Jain, Mukul R., Bahekar, Rajesh
Format: Article
Language:English
Subjects:
Administration, Oral
Animals
Antagonist
antagonists
Benzyl Compounds - administration & dosage
Benzyl Compounds - chemistry
Benzyl Compounds - pharmacology
Biological and medical sciences
Blood Glucose - drug effects
chemistry
Diabetes
Diabetes Mellitus, Type 2 - drug therapy
Dose-Response Relationship, Drug
Drug Discovery
Focal Adhesion Protein-Tyrosine Kinases - antagonists & inhibitors
Gene Products, tat - antagonists & inhibitors
Glucocorticoid
glucocorticoid receptors
Humans
hypoglycemic agents
Hypoglycemic Agents - administration & dosage
Hypoglycemic Agents - chemistry
Hypoglycemic Agents - pharmacology
Indexing in process
liver
Liver - chemistry
Liver - drug effects
Liver - metabolism
Liver Selective
Male
Medical sciences
Mice
Mice, Obese
Models, Molecular
Molecular Structure
Non-steroidal
Pharmacology. Drug treatments
Rats
Rats, Sprague-Dawley
Receptors, Glucocorticoid - antagonists & inhibitors
Structure-Activity Relationship
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Summary:Series of benzyl-phenoxybenzyl amino-phenyl acid derivatives are reported as non-steroidal GR antagonist. The lead compound 8g exhibited significant oral antidiabetic and antihyperlipidemic effects (in vivo), along with liver selectivity. Series of benzyl-phenoxybenzyl amino-phenyl acid derivatives (8a–q) are reported as non-steroidal GR antagonist. Compound 8g showed excellent h-GR binding and potent antagonistic activity (in vitro). The lead compound 8g exhibited significant oral antidiabetic and antihyperlipidemic effects (in vivo), along with liver selectivity. These preliminary results confirm discovery of potent and liver selective passive GR antagonist for the treatment of T2DM.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2012.07.078