Discovery of (2R)-2-(3-{3-[(4-Methoxyphenyl)carbonyl]-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl}phenoxy)butanoic Acid (MK-0533): A Novel Selective Peroxisome Proliferator-Activated Receptor γ Modulator for the Treatment of Type 2 Diabetes Mellitus with a Reduced Potential to Increase Plasma and Extracellular Fluid Volume

Abstract

Peroxisome proliferator-activated receptor gamma (PPARgamma) agonists are used to treat type 2 diabetes mellitus (T2DM). Widespread use of PPARgamma agonists has been prevented due to adverse effects including weight gain, edema, and increased risk of congestive heart failure. Selective PPARgamma modulators (SPPARgammaMs) have been identified that have antidiabetic efficacy and reduced toxicity in preclinical species. In comparison with PPARgamma full agonists, SPPARgammaM 6 (MK0533) displayed diminished maximal activity (partial agonism) in cell-based transcription activation assays and attenuated gene signatures in adipose tissue. Compound 6 exhibited comparable efficacy to rosiglitazone and pioglitazone in vivo. However, with regard to the induction of untoward events, 6 displayed no cardiac hypertrophy, attenuated increases in brown adipose tissue, minimal increases in plasma volume, and no increases in extracellular fluid volume in vivo. Further investigation of 6 is warranted to determine if the improvement in mechanism-based side effects observed in preclinical species will be recapitulated in humans.

Nuclear Receptors and Their Selective Pharmacologic Modulators

“…Nuclear Receptors and Their Selective Modulators increased plasma volume, extracellular fluid, and heart weight after 7 days of treatment, MK0533 did not produce significant increases in those same parameters in Zucker fa/fa rats (Acton et al, 2009). Although these preclinical data showed promise, a phase 2 clinical trial for MK0533 by Merck was terminated due to lack of glycemic and body fluid benefits over pioglitazone (Merck; http://clinicaltrialsgov/ct2/show/ NCT00543959).…”

Effects of Chronic Rosiglitazone Treatment on Renal Handling of Salt and Water in Rats With Volume-Overload Congestive Heart Failure

“…This relatively high dose of RGZ is in the range that was shown to produce a significant increase in extracellular fluid (ECF) volume in Zucker rats. 30 Urine output and sodium excretion were monitored daily and cumulative U Na V was calculated over the experimental period. Hematocrit and body weight were measured at 8-to 10-day intervals and on the last day of experiments.…”

Design, Synthesis, and Biological Evaluation of Indole Biphenylcarboxylic Acids as PPARγ Antagonists

“…25,26 Lastly, Merck identified MRL-24 as a potent partial agonist of PPARγ, which was ultimately optimized and advanced into clinical trials as MK-0533. 12,27 Roughly two dozen analogues in each series were synthesized and screened in both a PPARγ binding assay using a competitive Lanthascreen assay format and a fluorescently labeled probe as well as in a transactivation assay using PPARγ-GAL4 and a UAS-Luciferase reporter assay system in an effort to help identify which series held the most promise. Compounds that exhibited minimum transactivation in GAL-4 were profiled using full-length PPARγ and a 5xPPRE-Luciferase reporter construct.…”