Optimization of amide-based inhibitors of soluble epoxide hydrolase with improved water solubility.
Soluble epoxide hydrolase (sEH) plays an important role in the metabolism of endogenous chemical mediators involved in the regulation of blood pressure and inflammation. 1,3-Disubstituted ureas with a polar group located on the fifth atom from the carbonyl group of urea function are active inhibitors of sEH both in vitro and in vivo. However, their limited solubility in water and relatively high melting point lead to difficulties in formulating the compounds and poor in vivo efficacy. To improve these physical properties, the effect of structural modification of the urea pharmacophore on the inhibition potencies, water solubilities, octanol/water partition coefficients (log P), and melting points of a series of compounds was evaluated. For murine sEH, no loss of inhibition potency was observed when the urea pharmacophore was modified to an amide function, while for human sEH 2.5-fold decreased inhibition was obtained in the amide compounds. In addition, a NH group on the right side of carbonyl group of the amide pharmacophore substituted with an adamantyl group (such as compound 14) and a methylene carbon present between the adamantyl and amide groups were essential to produce potent inhibition of sEH. The resulting amide inhibitors have 10-30-fold better solubility and lower melting point than the corresponding urea compounds. These findings will facilitate synthesis of sEH inhibitors that are easier to formulate and more bioavailable.
Kim
In-Hae
IH
Department of Entomology and University of California Davis Cancer Center, University of California, One Shields Avenue, Davis, California 95616, USA.
Heirtzler
Fenton R
FR
Morisseau
Christophe
C
Nishi
Kosuke
K
Tsai
Hsing-Ju
HJ
Hammock
Bruce D
BD
D020003:1-Octanol; D000218:Adamantane / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000737:chemistry; D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry*; D000818:Animals; D002087:Butyrates / Q000138:chemical synthesis / Q000737:chemistry; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D012995:Solubility; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014508:Urea / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000737:chemistry; D014867:Water
D000577:Amides; D002087:Butyrates; D014867:Water; D014508:Urea; D004851:Epoxide Hydrolases; D020003:1-Octanol; D000218:Adamantane