With this proposal we aim to further the development of novel and safe oral inhibitors of sEH for the treatment of peripheral neuropathy in diabetic patients. Preclinical studies with our candidate EC5026 demonstrated efficacy for diabetic neuropathy. EicOsis has selected EC5026 for its efficacy with good PK/ADME properties and stability to enter further development stages for this indication. EicOsis also tested the compound and a backup in vitro for off target effects against an array of enzymes, determined the potential inhibition of major cytochrome P450 enzymes, and tested for de-risking with a contract research laboratory. EicOsis has used these data as a basis for an application to work with Blueprint Development Teams to create a development plan and initiate studies to test the safety of EC5026 in Phase 1 clinical trials. To further develop the compounds selected from the completed Phase I application we propose here to radiolabel the candidate and backup to carry out detailed metabolism studies and develop the label as a tracer for human Phase I clinical trial. Additionally we propose to use conventional material to test for off-target toxicity in vivo and to explore the breadth of activity of the inhibitors in alternate pain models. The studies are designed to address understanding metabolism and the spectrum of activity which if lacking often prevent drugs from being developed. The results will empower scientists in the pharmaceutical industry with critical data that speaks to the wider spectrum of activity of sEH inhibitors as analgesics of the future.

Public Health Relevance

Data collected over the past decade indicate the unique characteristics of inhibitors of sEH as analgesics. The overarching goal of EicOsis is to develop a drug candidate for IND enabling studies for the treatment of neuropathic pain. Here we outline studies to further explore the in vivo metabolism and potential off target toxicity of the sEH inhibitors as well as their broader efficacy in alternate pain models.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Small Business Innovation Research Grants (SBIR) - Phase II (R44)
Project #
5R44ES025598-03
Application #
9232153
Study Section
Special Emphasis Panel (ZRG1-ETTN-M (11)B)
Program Officer
Shaughnessy, Daniel
Project Start
2014-09-22
Project End
2018-02-28
Budget Start
2017-03-01
Budget End
2018-02-28
Support Year
3
Fiscal Year
2017
Total Cost
$705,128
Indirect Cost
Name
Eicosis, LLC
Department
Type
Domestic for-Profits
DUNS #
078707261
City
Davis
State
CA
Country
United States
Zip Code
95618
Wagner, K; Lee, K S S; Yang, J et al. (2017) Epoxy fatty acids mediate analgesia in murine diabetic neuropathy. Eur J Pain 21:456-465
Trindade-da-Silva, Carlos Antonio; Bettaieb, Ahmed; Napimoga, Marcelo Henrique et al. (2017) Soluble Epoxide Hydrolase Pharmacological Inhibition Decreases Alveolar Bone Loss by Modulating Host Inflammatory Response, RANK-Related Signaling, Endoplasmic Reticulum Stress, and Apoptosis. J Pharmacol Exp Ther 361:408-416
Wagner, Karen M; McReynolds, Cindy B; Schmidt, William K et al. (2017) Soluble epoxide hydrolase as a therapeutic target for pain, inflammatory and neurodegenerative diseases. Pharmacol Ther 180:62-76
Inceoglu, Bora; Bettaieb, Ahmed; Trindade da Silva, Carlos A et al. (2015) Endoplasmic reticulum stress in the peripheral nervous system is a significant driver of neuropathic pain. Proc Natl Acad Sci U S A 112:9082-7