ABSTRACT
Diabetes is affecting the life of millions of people. A large proportion of diabetic patients suffer from severe complications such as neuropathic pain, and current treatments for these complications have deleterious side effects. Thus, alternate therapeutic strategies are needed. Recently, the elevation of epoxy-fatty acids through inhibition of soluble epoxide hydrolase (sEH) was shown to reduce diabetic neuropathic pain in rodents. In this report, we describe a series of newly synthesized sEH inhibitors with at least 5-fold higher potency and doubled residence time inside both the human and rodent sEH enzyme than previously reported inhibitors. These inhibitors also have better physical properties and optimized pharmacokinetic profiles. The optimized inhibitor selected from this new series displayed improved efficacy of almost 10-fold in relieving pain perception in diabetic neuropathic rats as compared to the approved drug, gabapentin, and previously published sEH inhibitors. Therefore, these new sEH inhibitors could be an attractive alternative to treat diabetic neuropathy in humans.
Subject(s)
Diabetic Neuropathies/drug therapy , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Epoxide Hydrolases/antagonists & inhibitors , Administration, Oral , Amines/pharmacology , Analgesics/pharmacology , Animals , Biological Availability , Chemistry Techniques, Synthetic , Crystallography, X-Ray , Cyclohexanecarboxylic Acids/pharmacology , Diabetes Mellitus, Type 1/complications , Diabetic Neuropathies/metabolism , Drug Design , Enzyme Inhibitors/pharmacokinetics , Gabapentin , Humans , Male , Mice , Molecular Targeted Therapy , Neuralgia/drug therapy , Rats, Sprague-Dawley , Solubility , Structure-Activity Relationship , Time Factors , gamma-Aminobutyric Acid/pharmacologyABSTRACT
Bacterial cells control resistance to the macrolide antibiotic erythromycin using the MphR(A) repressor protein. Erythromycin binds to MphR(A), causing release of the PmphR promoter, activating expression of the 2'-phosphotransferase Mph(A). We engineered the MphR(A)/promoter system to, in conjunction with a light-activatable derivative of erythromycin, enable photochemical activation of gene expression in E. coli. We applied this photochemical gene switch to the construction of a light-triggered logic gate, a light-controlled band-pass filter, as well as spatial and temporal control of gene expression.