Abdul Hye Khan, PhD
(414) 955-4659 | Fax: (414) 955-6545
Epoxyeicosatrienoic Acid Analog Based Drug Development
Lipid signaling in the arachidonic acid cascade is an important therapeutic target for many human diseases. Arachidonic acid, an essential fatty acid, is metabolized by cytochrome P450 epoxygenase system to epoxyeicosatrienoic acids (EETs). EETs have been investigated as autocrine and paracrine mediators with numerous biological actions including, vasodilation, anti-inflammatory, anti-oxidant, and anti-apoptotic. With these promising biological actions, concept has been led that EETs and its metabolic pathway can be therapeutically targeted for cardiovascular drug development. In this effort, one drug-development approach has been to maintain/increase endogenously produced EETs level by preventing their metabolism via soluble epoxide hydrolase (sEH). Indeed, today the development of sEH inhibitors as potential therapeutics reached to the point where they have been evaluated in human. However, the major drawbacks of sEH inhibitors are that they result in a generalized increase in EETs and that their effectiveness depends entirely on cytochrome P450 epoxygenase-mediated EET generation. This is an important limitation because many kidney and cardiovascular diseases are associated with impaired epoxygenase generation of EETs. It is, therefore very likely that if CYP epoxygenase mediated EET generation is impaired then sEH inhibition will have a negligible effect on EET levels in these pathological conditions. These limitations of sEH inhibitor prompted a second approach of EET-based drug development and idea of EET analogs originates. My research focuses on EET-based drug development using this approach. In collaboration with a prominent group of medicinal chemists we are developing series of novel therapeutically promising EET analogs. We are studying therapeutic efficacy and exploring mechanism of actions of these EET analogs in different disease conditions with a long-term goal of developing novel EET-based drug to treat kidney and cardiovascular diseases.