Study the effect of drug resident time on in vivo efficacy (844.6)

Abstract

When developing a new drug, it is difficult to predict from in vitro parameters to in vivo efficacy. It is generally accepted that drugs with the strong interactions with their target are more likely to show better efficacy. Therefore, thermodynamic parameter: dissociation constant or inhibition constant (Ki) are often considered as the most important factor to be determined as the first screening to prioritize the drug candidates. However, the kinetic parameter: the dissociation rate constant (koff) of the drugs is often neglected although several reports suggested that koff is as important as or more than Ki to estimate in vivo efficacy.Soluble epoxide hydrolase (sEH) has been proven to play an important role on regulating important lipid mediators, epoxy‐polyunsaturated fatty acid. Inhibition of sEH has been showed to be beneficial to human health in several aspects, anti‐inflammatory, analgesic and promoting tissue regeneration. We recently synthesized a series of new sEH inhibitors with different Kis and koffs. These inhibitors will be used as tools to test if koff can predict in vivo efficacy as equal as or better than the Ki.Here, a series of inhibitors with improved in vitro efficacy will be reported. Our in vivo results suggested that koff is crucial parameters to affect drug efficacy in an alternate way.Grant Funding Source: National Institute of Environ‐ mental Health Sciences (NIEHS) grant ES002710