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 to be much less potent. Although the E-isomer showed a moderate PPAR gamma 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 PPAR gamma agonist properties.
Neogi
Partha
P
Department of Chemistry, Calyx Therapeutics Inc., 3513 Breakwater Avenue, Hayward, CA 94545, USA. p.neogi@att.net
Lakner
Fredrick J
FJ
Medicherla
Satyanarayana
S
Cheng
Jin
J
Dey
Debendranath
D
Gowri
Maya
M
Nag
Bishwajit
B
Sharma
Somesh D
SD
Pickford
Lesley B
LB
Gross
Coleman
C
D000818:Animals; D001786:Blood Glucose / Q000032:analysis / Q000378:metabolism; D002934:Cinnamates / Q000737:chemistry*; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000378:metabolism; D004195:Disease Models, Animal; D007004:Hypoglycemic Agents / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D007536:Isomerism; D051379:Mice; D010666:Phenylpropionates / Q000138:chemical synthesis / Q000494:pharmacology; D011355:Prodrugs / Q000138:chemical synthesis / Q000494:pharmacology; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists / Q000096:biosynthesis; D013329:Structure-Activity Relationship; D045162:Thiazolidinediones / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D014157:Transcription Factors / Q000819:agonists / Q000096:biosynthesis
D001786:Blood Glucose; D002934:Cinnamates; D007004:Hypoglycemic Agents; D010666:Phenylpropionates; D011355:Prodrugs; D018160:Receptors, Cytoplasmic and Nuclear; D045162:Thiazolidinediones; D014157:Transcription Factors; C029010:cinnamic acid