Design and synthesis of highly potent and selective human peroxisome proliferator-activated receptor α agonists

Transcriptome Analysis of K-877 (a Novel Selective PPARα Modulator (SPPARMα))-Regulated Genes in Primary Human Hepatocytes and the Mouse Liver

“…As revealed by the microarray analysis, K-877 treatment resulted in an increase in the number of up-or downregulated mRNAs in a dose-dependent manner (Supplementary Table 1). In previous preclinical animal studies 4,5) , the effects of 1 to 10 mg/kg/day doses of K-877 were compared with that of 100 mg/kg/day of fenofibrate; 645 and 603 probe sets were upregulated by 3 mg/kg/day of K-877 and 100 mg/kg/day of fenofibrate treatment, respectively, while, 627 and 538 probe sets were downregulated, respectively (Supplementary Table 1). Among these probe sets, 512 and 426 were commonly up-or downregulated (Supplementary Fig.…”

“…To generate new chemical entities that maximize the beneficial effects and minimize the adverse effects of fibrates, selective PPAR modulators (SPPARM ) have been actively pursued as the next generation of lipid-lowering drugs 3,4) . K-877 is a novel SPPARM that enhances the PPAR activity and selectivity by introducing a 2-aminobenzoxazole ring and phenoxyalkyl chain into fibric acid 5) . K-877 has greater PPAR activation potency than other fibrates, with a lower EC50 value and higher degree of subtype selectivity ( 1,000-fold subtype selectivity).…”

“…K-877 has greater PPAR activation potency than other fibrates, with a lower EC50 value and higher degree of subtype selectivity ( 1,000-fold subtype selectivity). In preclinical studies, K-877 has been shown to have a greater TG-lowering effect than fenofibrate in normolipidemic rats with a reduced amount of liver weight gain 5) . Additionally, K-877 treatment induces a more pronounced increase in the plasma h-apoAI levels in human apoAI-I transgenic mice than fenofibrate.…”

Microwave‐Assisted Synthesis, Hypolipidemic and Hypoglycemic Activity of Some Novel 2‐(4‐(2‐Amino‐6‐(4‐substituted phenyl)‐pyrimidin‐4‐yl)‐phenoxy)‐2‐methyl Propanoic Acid Derivatives

“…It was observed that phenoxy isobutyric acid pharmacophores have been frequently used in the synthesis of hypolipidemic agents [3][4][5][6][7][8]. Phenoxy isobutyric acid moiety was frequently coupled with heterocyclic nucleus such as benzoxazole [3], pyrimidine [9], thiazole [10], trifluoromethane sulfonamide [11], thiadiazole [12] and morpholine [13] to have more potent antihyperlipidemic agent.…”

“…Phenoxy isobutyric acid moiety was frequently coupled with heterocyclic nucleus such as benzoxazole [3], pyrimidine [9], thiazole [10], trifluoromethane sulfonamide [11], thiadiazole [12] and morpholine [13] to have more potent antihyperlipidemic agent.…”