Soluble epoxide hydrolase (sEH) inhibitors function to stabilize biologically active lipid metabolites responsible for regulating homeostatic biological processes. The presence of these beneficial lipid metabolites in tissues and their metabolism by sEH into less active diols was first reported 30 years ago, and many subsequent advances were facilitated by several academic laboratories, principally The University of California at Davis. These efforts led to the identification of a large chemical library of potent sEH inhibitors. Researchers correlated enzyme potency with in vivo efficacy using Ki and target occupancy to identify lead compounds that were then tested for efficacy in a variety of models and identified sEH inhibitors as a potential and promising therapy for human pathologies including but not limited to pain, seizure, chronic obstructive pulmonary disorder, and arthritis. Consequently, the research was positioned for translation into clinical development. EicOsis was formed and incorporated to license the technology from the University of California and navigate through the ‘Valley of Death’ – a term coined to describe the funding challenges between basic research and proof of efficacy in humans. In order to move through this stage, EicOsis successfully used creative strategies that capitalized on a small business’ ability to move quickly and efficiently, and leveraged existing academic collaborations to advance lead optimization in a start‐up environment.EicOsis quickly characterized physical properties of the lead compounds and found they had poor solubility and a high melting point. Slight modifications in the structure significantly lowered the melting point and improved solubility which resulted in new IP. These new compounds were then tested, either in‐house or with collaborators, in traditional safety, PK and pain efficacy studies, as well as assays that differentiated peripherally acting compounds from those acting on the central nervous system. Ultimately, these strategies led to the identification of a peripherally restricted lead candidate and back‐up that is both peripherally and centrally active. Both compounds have an efficacy and safety profile in rodents exceeding that of FDA approved neuropathic pain drugs, opioids, and NSAIDs, without adverse effects on the central nervous system, cardiovascular system, or GI system. Preclinical data also indicate there is unlikely to be addiction liability.Here, we present an overview of the strategies and results that culminated in successive rounds of non‐dilutive funding from NIH to support development of sEH inhibitors through Phase 1 clinical trials in healthy volunteers. Given that sEH inhibitors represent a very novel drug target that is still largely unknown to potential investors and to the venture capital community, this provides essential support for future Phase 2 proof‐of‐concept clinical trials in diabetic painful neuropathy.Support or Funding InformationR43/44ES025598UH2NS094258