A PPAR Pan Agonist, MHY2013 Alleviates Age-Related Hepatic Lipid Accumulation by Promoting Fatty Acid Oxidation and Suppressing Inflammation.

Nonalcoholic fatty liver disease (NAFLD) is frequently observed in obese and aged individuals. Peroxisome proliferator-activated receptors (PPARs) play a role in regulating hepatic lipid accumulation, a hallmark of NAFLD development. A PPAR pan agonist, 2-(4-(5,6-methylenedioxybenzo[d]thiazol-2-yl)-2-methylphenoxy)-2-methylpropanoic acid (MHY2013) has been shown to prevent fatty liver formation and insulin resistance in obese mice (db/db) model. However, the beneficial effects of MHY2013 in aged model remain unknown. In this study, we investigated whether MHY2013 alleviates hepatic lipid accumulation in aged Sprague-Dawley (SD) rats. We confirmed that MHY2013 increased the activities of three PPAR subtypes in HepG2 cells using luciferase assay. When administered orally in aged SD rats, MHY2013 markedly decreased the hepatic triglyceride levels without changes in body weight. Regarding underlying mechanisms, MHY2013 increased the mRNA levels of lipid oxidation-related genes, including carnitine palmitoyltransferase 1 (CPT1) and peroxisomal acyl-CoA oxidase 1 (ACOX1), without apparent change in the mRNA expression of lipogenesis-related genes. Furthermore, MHY2013 significantly increased systemic fibroblast growth factor 21 (FGF21) and adiponectin levels and suppressed inflammatory mRNA expression in the liver. In conclusion, MHY2013 alleviated age-related hepatic lipid accumulation, in part by upregulating ß-oxidation signaling and suppressing inflammation in the liver. Therefore, MHY2013 is a potential pharmaceutical agent for treating age-related hepatic lipid accumulation.

PPARα activation by MHY908 attenuates age-related renal inflammation through modulation of the ROS/Akt/FoxO1 pathway.

2-[4-(5-Chlorobenzothiazothiazol-2-yl)phenoxy]-2-methyl-propionic acid (MHY908) has been shown to prevent insulin resistance-induced hyperinsulinemia in aged rats. However, the mechanism underlying MHY908-mediated amelioration of renal inflammation with insulin resistance during aging remains unknown. This study investigated the effects of MHY908 on age-related changes in the IRS/Akt/forkhead box (FoxO) 1 signaling pathway in the kidneys of aged rats and HEK293T cells. Experiments were performed in young, old, and MHY908-fed old rats (1mg or 3mg/kg/day MHY908 for 4 weeks). We found that MHY908-fed old rats suppressed phosphorylation of IRS/Akt and induced FoxO1 activation, leading to increased expression of MnSOD and catalase. In addition, in insulin-treated cells, MHY908 prevented the FoxO1 inactivation and increased the expression of MnSOD and catalase by inactivating IRS and Akt. In contrast, NF-κB signaling pathway decreased with MHY908 treatment in insulin-treated cells. Furthermore, MHY908 exclusively activated peroxisome proliferator-activated receptor (PPAR) α in the kidneys, leading to the inhibition of insulin-induced NADPH oxidase subunit 4 (NOX4)-derived reactive oxygen species (ROS) generation and FoxO1 inactivation. In conclusion, MHY908 improved the hyperinsulinemia-induced pro-inflammatory response through NF-κB inactivation and FoxO1 activation in aged rat kidneys. These phenomena suggest that PPARα activation by MHY908 attenuates NOX4-derived ROS generation in response to insulin.

Design, synthesis, and antimelanogenic effects of (2-substituted phenyl-1,3-dithiolan-4-yl)methanol derivatives.

The authors designed and synthesized 17 (2-substituted phenyl-1,3-dithiolan-4-yl) methanol (PDTM) derivatives to find a new chemical scaffold, showing excellent tyrosinase-inhibitory activity. Their tyrosinase-inhibitory activities were evaluated against mushroom tyrosinase at 50 µM, and five of the PDTM derivatives (PDTM3, PDTM7-PDTM9, and PDTM13) were found to inhibit mushroom tyrosinase more than kojic acid or arbutin, the positive controls. Of seventeen PDTMs, PDTM3 (half-maximal inhibitory concentration 13.94±1.76 µM), with a 2,4-dihydroxyphenyl moiety, exhibited greatest inhibitory effects (kojic acid half-maximal inhibitory concentration 18.86±2.14 µM). Interestingly, PDTM compounds with no hydroxyl group, PDTM7-PDTM9, also had stronger inhibitory activities than kojic acid. In silico studies of interactions between tyrosinase and the five PDTMs suggested their binding affinities were closely related to their tyrosinase-inhibitory activities. Cell-based experiments performed using B16F10 mouse-skin melanoma cells showed that PDTM3 effectively inhibited melanogenesis and cellular tyrosinase activity. A cell-viability study conducted using B16F10 cells indicated that the antimelanogenic effect of PDTM3 was not attributable to its cytotoxicity. Kinetic studies showed PDTM3 competitively inhibited tyrosinase, indicating binding to the tyrosinase-active site. We found that PDTM3 with a new chemical scaffold could be a promising candidate for skin-whitening agents, and that the 1,3-dithiolane ring could be used as a chemical scaffold for potent tyrosinase inhibition.

Physiological characterization of a novel PPAR pan agonist, 2-(4-(5,6-methylenedioxybenzo[d]thiazol-2-yl)-2-methylphenoxy)-2-methylpropanoic acid (MHY2013).

Recently, agonists targeting multiple peroxisome proliferator-activated receptors (PPARs) have been developed to improve metabolic disorders and minimize the side effects of selective PPAR agonists such as weight gain and dyslipidemia. We newly synthesized six 2-methyl-2-(o-tolyloxy)propanoic acid derivatives based on the structure of a well-known PPAR pan agonist, bezafibrate. Of six compounds, MHY2013 was screened as the strongest activator of three PPAR subtypes based on protein docking simulation and luciferase assays. When treated orally in db/db mice, MHY2013 ameliorated obesity-induced insulin resistance, dyslipidemia, and hepatic steatosis without changes of the body weight and levels of liver and kidney injury markers. MHY2013 decreased the serum triglyceride and fatty acid levels, which is associated with an increase in fatty acid oxidation signaling in the liver and thermogenic signaling on white adipose tissue, respectively. Furthermore, MHY2013 markedly increased serum levels of insulin-sensitizing hormones including fibroblast growth factor 21 (FGF21) and adiponectin. In conclusion, this study suggests that, MHY2013 is a novel PPAR pan agonist that improves obesity-induced insulin resistance, dyslipidemia and hepatic steatosis and elevates insulin-sensitizing hormones in the blood.

Tyrosinase inhibitors: a patent review (2011-2015).

INTRODUCTION: Tyrosinase is responsible for melanin production. The overproduction of melanin causes many skin disorders. The inhibition of tyrosinase activity would appear to be the most rational and explicit way of overcoming these issues. AREAS COVERED: Thirty eight patents on synthetic tyrosinase inhibitors issued since 2011 were reviewed. Inhibitors were categorized by chemical structure and assigned to eight classes. Information on potent inhibitors in each class is provided. EXPERT OPINION: Many tyrosinase inhibitors of natural or synthetic origin have been identified, but very few are qualified for clinical use. Thus medicinal scientists have to work more on the identification of potent and safe tyrosinase inhibitors. Various chemical scaffolds have been explored. Among them, the scaffolds such as resorcinol, biaryl, imidazolethione, ß-phenyl-α,ß-unsaturated carbonyl, and some double strand oligonucleotides have shown high tyrosinase inhibition, low toxicities, and great potencies. Detail structure activity relationship studies of these potential scaffolds could provide directions for a new and potent tyrosinase inhibitors. Furthermore new trends, such as the use of synergistic phenomena, salt formation, drug repositioning and designing of multi-targeted tyrosinase inhibitors could expand search areas for much improved tyrosinase inhibitors.

(E)-2-Cyano-3-(substituted phenyl)acrylamide analogs as potent inhibitors of tyrosinase: A linear ß-phenyl-α,ß-unsaturated carbonyl scaffold.

In this study, we synthesized (E)-2-cyano-3-(substituted phenyl)acrylamide (CPA) derivatives which possess a linear ß-phenyl-α,ß-unsaturated carbonyl scaffold and examined their inhibitory activities against tyrosinase. CPA analogs exerted inhibitory activity against mushroom tyrosinase. Results from the docking simulation indicated that CPA2 could bind directly to the active site of mushroom tyrosinase and the binding affinity of CPA2 for tyrosinase might be higher than that of kojic acid, a well-known potent tyrosinase inhibitor. In B16F10 cells, CPA2 significantly suppressed tyrosinase activity and melanogenesis in a dose-dependent manner. At the concentration of 25µM, CPA2 exhibited tyrosinase inhibitory activity comparable to that of kojic acid with no cytotoxic effect. Results from the present study suggest that CPA2 bearing a linear ß-phenyl-α,ß-unsaturated carbonyl scaffold may be the potential candidate for treatment of diseases associated with hyperpigmentation and that a linear ß-phenyl-α,ß-unsaturated carbonyl scaffold might be closely related to potent tyrosinase inhibition.

Design, synthesis, and anti-melanogenic effects of (E)-2-benzoyl-3-(substituted phenyl)acrylonitriles.

BACKGROUND: Tyrosinase is the most prominent target for inhibitors of hyperpigmentation because it plays a critical role in melaninogenesis. Although many tyrosinase inhibitors have been identified, from both natural and synthetic sources, there remains a considerable demand for novel tyrosinase inhibitors that are safer and more effective. METHODS: (E)-2-Benzoyl-3-(substituted phenyl)acrylonitriles (BPA analogs) with a linear ß-phenyl-α,ß-unsaturated carbonyl scaffold were designed and synthesized as potential tyrosinase inhibitors. We evaluated their effects on cellular tyrosinase activity and melanin biosynthesis in murine B16F10 melanoma cells and their ability to inhibit mushroom tyrosinase activity. RESULTS: BPA analogs exhibited inhibitory activity against mushroom tyrosinase. In particular, BPA13 significantly suppressed melanin biosynthesis and inhibited cellular tyrosinase activity in B16F10 cells in a dose-dependent manner. A docking study revealed that BPA13 had higher binding affinity for tyrosinase than kojic acid. CONCLUSION: BPA13, which possesses a linear ß-phenyl-α,ß-unsaturated carbonyl scaffold, is a potential candidate skin-whitening agent and treatment for diseases associated with hyperpigmentation.

(Z)-2-(Benzo[d]thiazol-2-ylamino)-5-(substituted benzylidene)thiazol-4(5H)-one Derivatives as Novel Tyrosinase Inhibitors.

Inhibiting tyrosinase is an important goal to prevent melanin accumulation in skin and thereby to inhibit pigmentation disorders. Therefore, tyrosinase inhibitors are an attractive target in cosmetics and treatments for pigmentation disorders. However, only a few tyrosinase inhibitors are currently available because of their toxic effects to skin or lack of selectivity and stability. Here, we newly synthesized thirteen (Z)-2-(benzo[d]thiazol-2-ylamino)-5-(substituted benzylidene)thiazol-4(5H)-one derivatives and examined their effect on melanogenesis. Of these compounds, MHY2081 had the strongest inhibitory effect on tyrosinase without cytotoxicity in B16F10 melanoma cells. Consistently, melanogenesis was notably decreased by MHY2081 treatment. As an underlying mechanism, docking simulation showed that compared to kojic acid, a well-known competitive tyrosinase inhibitor which forms a hydrogen bond and aromatic interaction with tyrosinase, MHY2081 has stronger affinity with tyrosinase by forming three hydrogen bonds and a hydrophobic interaction with residues of tyrosinase. In parallel with this, Lineweaver-Burk plot analysis showed that MHY2081 is a strong competitive inhibitor of tyrosinase. In conclusion, MHY2081 may be a novel tyrosinase inhibitor for prevention and treatment of pigmentation disorders.

Inhibition of melanogenesis by 2-[4-(5-chlorobenzo[d]thiazol-2-yl)phenoxy]-2-methylpropanoic acid (MHY908).

Tyrosinase inhibitors might have potential use in cosmetic and medicinal products for the prevention of pigmentation disorders. However, only a few inhibitors are currently used due to their cytotoxicity, and lack of selectivity and stability. In this study, we synthesized several tyrosinase inhibitors and investigated their activity. To investigate the action of 2-[4-(5-chlorobenzo[d]thiazol-2-yl)phenoxy]-2-methylpropanoic acid (MHY908) specifically in the inhibition of melanogenesis, a mushroom tyrosinase activity assay was performed. We confirmed the inhibitory effect of MHY908 at various melanin concentrations using α-MSH-induced melanoma cells. Our results indicate that MHY908 potently inhibited mushroom tyrosinase activity (IC50 = 8.19 µM) in a dose-dependent manner. Through a docking simulation, we also analyzed its binding mode to inhibit tyrosinase activity. MHY908 also decreased melanin synthesis without inducing cytotoxicity. These results suggest that MHY908 is a good candidate for prevention and treatment of pigmentation disorders.