PAM-1616, a selective peroxisome proliferator-activated receptor γ modulator with preserved anti-diabetic efficacy and reduced adverse effects.
Peroxisome proliferator-activated receptor (PPAR) γ is known to be a key regulator of insulin resistance. PAM-1616 is a novel, non-thiazolidinedione small molecule compound synthesized in Dong-A Research Center. In this study, we characterized the pharmacological and safety profiles of PAM-1616 as a selective PPARγ modulator. PAM-1616 selectively binds to human PPARγ (IC(50), 24.1±5.6 nM) and is a partial agonist for human PPARγ with an EC(50) of 83.6±43.7 nM and a maximal response of 24.9±7.1% relative to the full agonist, rosiglitazone. PAM-1616 was selective for human PPARγ than for human PPARα (EC(50), 2658±828 nM) without activating human PPARδ, which makes it a selective modulator of PPARγ. Treatment of high fat diet-induced obese C57BL/6J mice with PAM-1616 for 21 days improved HOMA-IR. Furthermore, PAM-1616 significantly improved hyperglycemia in db/db mice with little side effect when orally administered at a dose of 1 mg/kg/day for 28 days. Intriguingly, PAM-1616 was seen to increase the gene expression of inducible glucose transporter (GLUT4), while it partially induced that of a fatty acid carrier, aP2 in 3T3-L1 adipocytes, and it also showed partial recruitment of an adipogenic cofactor, TRAP220 as compared to rosiglitazone. PAM-1616 did not cause a significant increase in plasma volume of ICR mice when orally administered at a dose of 10 mg/kg/day for 9 days. PAM-1616 increased the expression of fluid retention-inducing genes such as serum/glucocorticoid-regulated kinase (SGK)-1 to a lesser extent as compared to rosiglitazone in human renal epithelial cells. These results suggest that PAM-1616 acts as a selective modulator of PPARγ with excellent antihyperglycemic property. The differential modulation of target gene by PAM-1616 might contribute to the improved side effect profiles.
Kim
Mi-Kyung
MK
Dong-A Research Center, 47-5 Sanggal-dong, Giheung-gu, Yongin-si, Gyeonggi-do, 446-905, Republic of Korea.
Chae
Yu Na
YN
Choi
Song-hyen
SH
Moon
Ho Sang
HS
Son
Moon-Ho
MH
Bae
Myung-Ho
MH
Choi
Hyun-ho
HH
Hur
Youn
Y
Kim
Eunkyung
E
Park
Yoo Hoi
YH
Park
Chan Sun
CS
Kim
Jae Gyu
JG
Lim
Joong In
JI
Shin
Chang Yell
CY
D041721:3T3-L1 Cells; D017667:Adipocytes / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D006801:Humans; D006943:Hyperglycemia / Q000188:drug therapy* / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D007333:Insulin Resistance; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D047493:PPAR alpha / Q000235:genetics / Q000378:metabolism; D047494:PPAR delta / Q000235:genetics / Q000378:metabolism; D047495:PPAR gamma / Q000819:agonists*; D010666:Phenylpropionates / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000494:pharmacology; D013876:Thiophenes / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D014882:Water-Electrolyte Balance / Q000187:drug effects
C555905:2-ethoxy-3-(4-(3-methyl-5-(4-(3-methylisoxazol-5-yl)phenyl)thiophen-2-ylmethoxy)phenyl)propionic acid; D007004:Hypoglycemic Agents; D047493:PPAR alpha; D047494:PPAR delta; D047495:PPAR gamma; D010666:Phenylpropionates; D045162:Thiazolidinediones; D013876:Thiophenes; D000077154:Rosiglitazone