PAT5A: a partial agonist of peroxisome proliferator-activated receptor gamma is a potent antidiabetic thiazolidinedione yet weakly adipogenic.
PAT5A [5-[4-[N-(2-pyridyl)-(2S)-pyrrolidine-2-methoxyl]phenylmethylene[thiazolidine-2,4-dione, malic acid salt]], a chemically distinct unsaturated thiazolidinedione, activates peroxisome proliferator-activated receptor gamma (PPARgamma) submaximally in vitro with the binding affinity approximately 10 times less than that of rosiglitazone, a highly potent thiazolidinedione. PAT5A reduces plasma glucose level and improves insulin sensitivity in insulin resistant db/db mice, similar to that of rosiglitazone, while exerting a relatively weak adipogenic effect. In contrast to rosiglitazone, PAT5A inhibits cholesterol and fatty acid biosynthesis suggesting that PAT5A possesses a unique receptor-independent non-PPAR related property. PAT5A induces qualitatively similar but quantitatively different protease digestion patterns and interacts with PPARgamma differently than rosiglitazone. PAT5A shows differential cofactor recruitment and gene activation than that of rosiglitazone. Thus, the partial agonism of PAT5A to PPARgamma together with its receptor independent effects may contribute to its antidiabetic potency similar to rosiglitazone in vivo despite reduced affinity for PPARgamma. These biological effects suggest that PAT5A is a PPARgamma modulator that activates some (insulin sensitization), but not all (adipogenesis), PPARgamma-signaling pathways.
Misra
Parimal
P
Discovery Research, Dr Reddy's Laboratories Ltd, Bollaram Road, Miyapur, Hyderabad, India.
Chakrabarti
Ranjan
R
Vikramadithyan
Reeba K
RK
Bolusu
Gopalakrishnan
G
Juluri
Suresh
S
Hiriyan
Jagadheshan
J
Gershome
Cynthia
C
Rajjak
Abdul
A
Kashireddy
Papreddy
P
Yu
Songtao
S
Surapureddi
Sailesh
S
Qi
Chao
C
Zhu
Yi-Jun
YJ
Rao
M Sambasiva
MS
Reddy
Janardan K
JK
Ramanujam
Rajagopalan
R
D016475:3T3 Cells; D017667:Adipocytes / Q000187:drug effects* / Q000378:metabolism; D000818:Animals; D001665:Binding Sites; D002352:Carrier Proteins / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D051548:Histone Acetyltransferases; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D056913:Mediator Complex Subunit 1; D051379:Mice; D056920:Nuclear Receptor Coactivator 1; D011725:Pyridines / Q000494:pharmacology*; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists* / Q000378:metabolism; D000077154:Rosiglitazone; D013844:Thiazoles / Q000494:pharmacology*; D045162:Thiazolidinediones; D053778:Thiazolidines; D014157:Transcription Factors / Q000819:agonists* / Q000378:metabolism
C476679:(5-(4-(N-2-pyridyl)-(2S)-pyrrolidine-2-methoxyl)phenylmethylene(thiazolidine-2,4-dione, malic acid salt)); D002352:Carrier Proteins; D017362:Cyclic AMP Response Element-Binding Protein; D007004:Hypoglycemic Agents; C538856:Med1 protein, mouse; D056913:Mediator Complex Subunit 1; D011725:Pyridines; D018160:Receptors, Cytoplasmic and Nuclear; D013844:Thiazoles; D045162:Thiazolidinediones; D053778:Thiazolidines; D014157:Transcription Factors; D000077154:Rosiglitazone; C089946:2,4-thiazolidinedione; D051548:Histone Acetyltransferases; C538861:Ncoa1 protein, mouse; D056920:Nuclear Receptor Coactivator 1