Synthesis and properties of 1-[(3-fluoroadamantan-1-yl)methyl]-3-R-ureas and 1,1′-(alkan-1,n-diyl)bis{3-[(3-fluoroadamantan-1-yl)methyl]ureas} as promising soluble epoxide hydrolase inhibitors

Fluorine and chlorine substituted adamantyl-urea as molecular tools for inhibition of human soluble epoxide hydrolase with picomolar efficacy

“…Series of 1,3-disubstituted ureas ( 9, 10 ) and diadamantyl disubstituted diureas with fluorinated and chlorinated adamantane residues ( 11a–i , 12a–g and 12i ) was obtained previously by a multi-step procedure with a key stage being the reaction of 1-fluoro-3-(isocyanatomethyl)adamantane and 1-chloro-3-(isocyanatomethyl)adamantane with trans -4-((4-aminocyclohexyl)oxy)benzoic acid or the corresponding diamines. 23 , 24 Some physicochemical characteristics of the compounds are presented in Tables 1 and 2 .…”

“…The compounds 9 , 10 , 11a–i , 12a–g and 12i were obtained previously, following the method described in Refs. 23 , 24 .…”

“… 19 Perhaps this is due to the partial blocking of metabolically sensitive centres by halogen atoms, which is widely used in drug design 20–22 Previously, we synthesised series of fluorinated and chlorinated analogs of t -AUCB derivative 1b and diureas 2 , 13 , 14 namely compounds 9 , 10 , 11a–i , 12a–g and 12i. 23 , 24 Given the remarkable microsomal stability and inhibitory efficiency of compounds 3а , b we proposed to carry out the primary bioscreening of the series 9 , 10 , 11a–i , 12a–g and 12i . In this communication, we present results of biotesting, which showed an unexpectedly sharp increase in inhibitory activity of some compounds to picomolar concentration range.…”