Synthesis and structure–Activity relationship studies of cinnamic acid-based novel thiazolidinedione antihyperglycemic agents

A number of 2,4-thiazolidinedione derivatives of -phenyl substituted cinnamic acid were synthesized and studied for their PPAR agonist activity. The E-isomer of cinnamic acid, 11, showed moderate PPAR transactivation. The corresponding Z-isomer, 23, and double bond reduced derivative, 15, were found...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry 2003-09, Vol.11 (18), p.4059-4067
Main Authors: Neogi, Partha, Lakner, Fredrick J, Medicherla, Satyanarayana, Cheng, Jin, Dey, Debendranath, Gowri, Maya, Nag, Bishwajit, Sharma, Somesh D, Pickford, Lesley B, Gross, Coleman
Format: Article
Language:English
Subjects:
Animals
Biological and medical sciences
Blood Glucose - analysis
Blood Glucose - metabolism
Cinnamates - chemistry
Diabetes Mellitus, Type 2 - drug therapy
Diabetes Mellitus, Type 2 - metabolism
Disease Models, Animal
General and cellular metabolism. Vitamins
Hypoglycemic Agents - chemical synthesis
Hypoglycemic Agents - pharmacology
Hypoglycemic Agents - therapeutic use
Isomerism
Medical sciences
Mice
Pharmacology. Drug treatments
Phenylpropionates - chemical synthesis
Phenylpropionates - pharmacology
Prodrugs - chemical synthesis
Prodrugs - pharmacology
Receptors, Cytoplasmic and Nuclear - agonists
Receptors, Cytoplasmic and Nuclear - biosynthesis
Structure-Activity Relationship
Thiazolidinediones - chemical synthesis
Thiazolidinediones - pharmacology
Thiazolidinediones - therapeutic use
Transcription Factors - agonists
Transcription Factors - biosynthesis
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Summary:A number of 2,4-thiazolidinedione derivatives of -phenyl substituted cinnamic acid were synthesized and studied for their PPAR agonist activity. The E-isomer of cinnamic acid, 11, showed moderate PPAR transactivation. The corresponding Z-isomer, 23, and double bond reduced derivative, 15, were found to be much less potent. Although the E-isomer showed a moderate PPARγ transactivation, it demonstrated a strong glucose-lowering effect in a genetic rodent model of diabetes. Results of pharmacokinetic, metabolism and permeability studies are consistent with 11 being an active prodrug with an active metabolite, 14, that has similar glucose lowering and PPARγ agonist properties. Novel cinnamic acid based thiazolidinediones are synthesized and evaluated their PPARγ agonist activity.
ISSN:0968-0896
1464-3391
DOI:10.1016/S0968-0896(03)00393-6