PAR-1622 is a selective peroxisome proliferator-activated receptor γ partial activator with preserved antidiabetic efficacy and broader safety profile for fluid retention

Abstract

Peroxisome proliferator-activated receptor (PPAR) gamma is known to be a key regulator of insulin resistance. PAR-1622 is a novel small molecule compound synthesized in Dong-A research center. In this study, we characterized the pharmacological profiles of PAR-1622, a selective partial activator of PPARgamma. In transient transactivation assays, PAR-1622 [(S)-2-ethoxy-3(4-(5-(4-(5-(methoxymethyl)isoxazol-3-yl)phenyl)-3-methylthiophen-2-yl)methoxy)phenyl)propanoic acid] showed a partial activator against human PPARgamma with an EC(50) of 41 nM and a maximal response of 37% relative to the full agonist rosiglitazone without activating human PPARdelta. PAR-1622 was 56 folds more selective for human PPARgamma than for human PPARalpha (EC(50), 2304 nM), which means that it is a selective partial activator of PPARgamma. PAR-1622 also showed a partial activator against mouse PPARgamma with an EC(50) of 427 nM and a maximal response was 57% of that of rosiglitazone. INT-131, a selective PPARgamma partial agonist in clinical stage, also was a partial activator against human PPARgamma with an EC(50) of 83 nM and a maximal response achieved by INT-131 was 49% of that observed with full agonist rosiglitazone. In functional assays using human mesenchymal stem cells, PAR-1622 induced adipocyte differentiation, which was 3-fold more potent with a comparable maximum response compared to INT-131. Furthermore, PAR-1622 significantly improved hyperglycemia in db/db when orally administered at a dose of 1 mg/kg/day for 5 days. In hemodilution assays with Evans Blue, rosiglitazone significantly increased the plasma volume in ICR mice that were orally administered 30 mg/kg/day for 9 days; however, PAR-1622 showed no significant effects on plasma volume, similar to INT-131. These results suggest that PAR-1622 is a selective partial activator of PPARgamma and has excellent antihyperglycemic activities and a broad safety profile for fluid retention.

Selective PPARγ modulator INT131 normalizes insulin signaling defects and improves bone mass in diet-induced obese mice

“…However, there is accumulating evidence that undesirable side effects, including body weight gain, anemia, fluid retention, and congestive heart failure, were seen in type 2 diabetic patients or animals treated with these compounds (13,16,27). Recent studies have developed a number of selective peroxisome proliferator-activated receptor modulators, including T2384, FK614, and PAR-1622, all of which are partial PPAR␥ agonists (23,30,31). The beneficiary effect of these insulinsensitizing compounds is that antihyperglycemic activity occurred independently of typical side effects in diabetic animals (14).…”

“…The beneficiary effect of these insulinsensitizing compounds is that antihyperglycemic activity occurred independently of typical side effects in diabetic animals (14). Specifically, PAR-1622 or INT131 therapy does not increase plasma volume in ICR mice, whereas rosiglitazone therapy increases this (23,26). Collectively, these data raise Fig.…”

Cytotoxic Capacity of IL-15-Stimulated Cytokine-Induced Killer Cells Against Human Acute Myeloid Leukemia and Rhabdomyosarcoma in Humanized Preclinical Mouse Models

“…But, CIK cell movement via the blood circulation and CIK cell expansion at tumor sites depended on the number of CIK cells infused. Some reports showed that CIK cells first entered into the lung, after inoculation of nude mice (Hazelrigg et al, 2002; Kim et al, 2009), peaked there within 2–6 h after injection, then declined, and re-distributed to organs such as liver, spleen, and kidney within 24 h. Another report demonstrated that CIK cells infused via the tail vein homed directly to the RES (Li et al, 2011). In contrast, in our study aggregation and expansion of infused CIK cells mostly occurred in BM and spleen at the time of analysis.…”

Structural Insight Into the Crucial Role of Ligand Chirality in the Activation of PPARs by Crystallographic Methods

“…For PAR-5359 (67), which was claimed to be the first compound with balanced activities for PPAR and PPAR in vivo as well in vitro, the utilization as a pharmacological tool in elucidating the complex roles of PPAR / dual agonists was suggested [88]. PAR-1622 (68), on the contrary, is a selective modulator of PPAR (SPPAR M) with excellent antihyperglycemic activity and a broader safety margin against fluid retention compared to rosiglitazone [89]. These findings confirmed that partial activators of PPAR may be a promising approach for developing new drugs for the treatment of type 2 diabetes.…”

“…(19). The effects of chirality on the activity of these fivemembered "cyclized fibrates" were investigated by comparing the activity of the two pairs of enantiomers from the 2-ethyl-and 2-isopropyl-substituted derivatives (88) and (89). Interestingly, it was found that (S)-88 and (R)-89 were about 400 times more potent than their respective isomers.…”