title: Optimized inhibitors of soluble epoxide hydrolase improve in vitro target residence time and in vivo efficacy.
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.
authors: Department of Entomology and Nematology, UCD Comprehensive Cancer Center, University of California Davis , One Shields Avenue, Davis, California 95616, United States.
authors: Kin Sing Stephen
authors: KS
authors: Lee
authors: Jun-Yan
authors: JY
authors: Liu
authors: Karen M
authors: KM
authors: Wagner
authors: Svetlana
authors: S
authors: Pakhomova
authors: Hua
authors: H
authors: Dong
authors: Christophe
authors: C
authors: Morisseau
authors: Samuel H
authors: SH
authors: Fu
authors: Jun
authors: J
authors: Yang
authors: Peng
authors: P
authors: Wang
authors: Arzu
authors: A
authors: Ulu
authors: Christina A
authors: CA
authors: Mate
authors: Long V
authors: LV
authors: Nguyen
authors: Sung Hee
authors: SH
authors: Hwang
authors: Matthew L
authors: ML
authors: Edin
authors: Alexandria A
authors: AA
authors: Mara
authors: Heike
authors: H
authors: Wulff
authors: Marcia E
authors: ME
authors: Newcomer
authors: Darryl C
authors: DC
authors: Zeldin
authors: Bruce D
authors: BD
authors: Hammock
mesh_terms: D000284:Administration, Oral; D000588:Amines / Q000494:pharmacology; D000700:Analgesics / Q000494:pharmacology; D000818:Animals; D001682:Biological Availability; D060326:Chemistry Techniques, Synthetic; D018360:Crystallography, X-Ray; D003509:Cyclohexanecarboxylic Acids / Q000494:pharmacology; D003922:Diabetes Mellitus, Type 1 / Q000150:complications; D003929:Diabetic Neuropathies / Q000188:drug therapy* / Q000378:metabolism; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors*; D000077206:Gabapentin; D006801:Humans; D008297:Male; D051379:Mice; D058990:Molecular Targeted Therapy; D009437:Neuralgia / Q000188:drug therapy; D017207:Rats, Sprague-Dawley; D012995:Solubility; D013329:Structure-Activity Relationship; D013997:Time Factors; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology
chemical_list: D000588:Amines; D000700:Analgesics; D003509:Cyclohexanecarboxylic Acids; D004791:Enzyme Inhibitors; D005680:gamma-Aminobutyric Acid; D000077206:Gabapentin; D004851:Epoxide Hydrolases