Diabetes and metabolic syndrome (MetS) afflicts close to 70 million Americans and diabetes accounts for close to half of all new cases of kidney failure. There is increasing interest in finding therapeutic targets and therapies that target multiple risk factors, thereby minimizing problems associated with multi-drug regimens in MetS and type 2 diabetic patients. The eicosanoid metabolome is altered in MetS and type 2 diabetes patients. The eicosanoid metabolome is altered in MetS and type 2 diabetes, and such alterations have been demonstrated to affect multiple factors including blood pressure, lipid levels, and insulin signaling. We have developed a novel chemical entity, 4-(phenyl-3-{3-[-(4-trifluoromethyl-phenyl)-ureido]-propyl}-pyrazol-1-yl)- benzenesulfonamide (PTUPB), that uniquely inhibits both soluble epoxide hydrolase (sEH) and cyclooxygenase (COX) and demonstrates potential as a therapeutic for MetS, type 2 diabetes and the associated kidney failure. Our long-term objective is to make significant steps towards an ultimate goal of an Investigational New Drug (IND) application for a novel chemical entity that uniquely alters eicosanoid metabolites and demonstrates potential as a therapeutic for MetS, type 2 diabetes. The overall objective of this application, which is the next step toward attainment of our long-term goal, is the pharmacological testing and the development and optimization of PTUPB-based COX-2/sEH inhibitors as a novel therapy for MetS and type 2 diabetes. Our central hypothesis is that inhibition of both COX-2 and sEH will uniquely alter eicosanoid metabolites to improve insulin signaling and renal function in MetS and type 2 diabetes. Our preliminary experiments demonstrate that the COX-2/sEH inhibitor, PTUPB has great therapeutic potential for treating multiple risk factors of MetS, type 2 diabetes and the associated kidney failure. Guided by strong preliminary data, our central hypothesis will be tested by pursuing three specific aims: 1) Optimize the PTUPB chemical scaffold to enhance the pharmacokinetic profile and the therapeutic potential; 2) Test the hypothesis that COX- 2/sEH inhibitors will manipulate eicosanoid metabolites to improve insulin signaling and pancreatic function, and decrease renal injury in MetS; 3) Test the hypothesis that COX-2/sEH inhibitors will manipulate eicosanoid metabolites to improve insulin signaling and pancreatic function, and decrease renal injury in type 2 diabetes. This project will conduct pharmacological testing of prototype small molecules in relevant animal models of MetS and type 2 diabetes. A major part of this proposal will be to utilize medicinal chemistry and computational approaches to optimize our early pre-therapeutic lead PTUPB. This contribution will be significant because it will open the door for identification and further development of COX-2/sEH inhibitors towards a therapeutic for diabetes and kidney disease.

Public Health Relevance

The proposed research is relevant to public health because diabetes and metabolic syndrome afflicts 70 million Americans. Kidney disease is a major complication in metabolic syndrome and type 2 diabetic patients and diabetes causes almost half of all new cases of kidney failure in 2008. This research project will validate that disruptio of eicosanoid metabolism is a key feature of type 2 diabetes and metabolic syndrome. We will address short and long-term efficacy and safety of PTUPB-based COX-2/sEH inhibitors. This is a required early-stage pharmacological target validation to test and validate our lead compound to safely alter disease progress and outcomes in humans. This is directly responsive to the mission of NIH NIDDK and PAR-13-007 because of the very substantial burden of diabetes, metabolic syndrome, and kidney disease in the USA.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK103616-03
Application #
9285798
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Pawlyk, Aaron C
Project Start
2015-08-20
Project End
2020-06-30
Budget Start
2017-07-01
Budget End
2018-06-30
Support Year
3
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Medical College of Wisconsin
Department
Pharmacology
Type
Schools of Medicine
DUNS #
937639060
City
Milwaukee
State
WI
Country
United States
Zip Code
53226
Li, Junyang; Zhou, Yali; Wang, Handong et al. (2017) COX-2/sEH dual inhibitor PTUPB suppresses glioblastoma growth by targeting epidermal growth factor receptor and hyaluronan mediated motility receptor. Oncotarget 8:87353-87363
Skibba, Melissa; Hye Khan, Md Abdul; Kolb, Lauren L et al. (2017) Epoxyeicosatrienoic Acid Analog Decreases Renal Fibrosis by Reducing Epithelial-to-Mesenchymal Transition. Front Pharmacol 8:406
Bettaieb, Ahmed; Koike, Shinichiro; Chahed, Samah et al. (2017) Podocyte-specific soluble epoxide hydrolase deficiency in mice attenuates acute kidney injury. FEBS J 284:1970-1986
Bettaieb, Ahmed; Koike, Shinichiro; Hsu, Ming-Fo et al. (2017) Soluble epoxide hydrolase in podocytes is a significant contributor to renal function under hyperglycemia. Biochim Biophys Acta 1861:2758-2765
Gangadhariah, Mahesha H; Dieckmann, Blake W; Lantier, Louise et al. (2017) Cytochrome P450 epoxygenase-derived epoxyeicosatrienoic acids contribute to insulin sensitivity in mice and in humans. Diabetologia 60:1066-1075
Campbell, William B; Imig, John D; Schmitz, James M et al. (2017) Orally Active Epoxyeicosatrienoic Acid Analogs. J Cardiovasc Pharmacol 70:211-224
Imig, John D (2016) Renal blood flow autoregulation: what are the contributions for nitric oxide or superoxide to modulate the myogenic response? Am J Physiol Renal Physiol 310:F1013-5
Imig, J D (2016) Epoxyeicosatrienoic Acids and 20-Hydroxyeicosatetraenoic Acid on Endothelial and Vascular Function. Adv Pharmacol 77:105-41
Hye Khan, Md Abdul; Hwang, Sung Hee; Sharma, Amit et al. (2016) A dual COX-2/sEH inhibitor improves the metabolic profile and reduces kidney injury in Zucker diabetic fatty rat. Prostaglandins Other Lipid Mediat 125:40-7
Sharma, Amit; Hye Khan, Md Abdul; Levick, Scott P et al. (2016) Novel Omega-3 Fatty Acid Epoxygenase Metabolite Reduces Kidney Fibrosis. Int J Mol Sci 17:

Showing the most recent 10 out of 11 publications