Design of bioavailable derivatives of 12-(3-adamantan-1-yl-ureido)dodecanoic acid, a potent inhibitor of the soluble epoxide hydrolase.
The soluble epoxide hydrolase (sEH) plays an important role in the metabolism of endogenous chemical mediators involved in blood pressure regulation and vascular inflammation. 12-(3-Adamantan-1-yl-ureido)-dodecanoic acid (AUDA, 1) is a very active inhibitor of sEH both in vitro and in vivo. However, its relatively high melting point and limited solubility in either water or oil-based solvents leads to difficulties in formulating the compound and often results in poor in vivo availability. We investigated the effect of derivatization of the acid functional group of inhibitor 1 on the inhibition potencies, physical properties, and pharmacokinetic properties. For human sEH, similar inhibition potency was obtained when the acid of compound 1 was modified to esters (2-15). The resulting compounds exhibited improved physical properties (23-66 degrees C lower melting point and 5-fold better solubility in oil). Pharmacokinetic studies showed that the esters possess improved oral bioavailability in mice. On the other hand, amide derivatives of AUDA 1 did not show significant improvement in inhibition potencies or physical properties (higher melting points and lower solubility). The esterification of 1 results in compounds that are easier to formulate in animal food and in triglycerides for gavage and other routes of administration, making it easier to study the biological effects of sEH inhibition in vivo.
Kim
In-Hae
IH
Department of Entomology and University of California Davis Cancer Center, University of California, One Shields Avenue, Davis, CA 95616, USA.
Nishi
Kosuke
K
Tsai
Hsing-Ju
HJ
Bradford
Tanya
T
Koda
Yasuko
Y
Watanabe
Takaho
T
Morisseau
Christophe
C
Blanchfield
Joanne
J
Toth
Istvan
I
Hammock
Bruce D
BD
D000218:Adamantane / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D000284:Administration, Oral; D000818:Animals; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000494:pharmacology*; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors*; D006801:Humans; D007850:Lauric Acids / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000494:pharmacology*; D008297:Male; D051379:Mice; D015394:Molecular Structure; D012995:Solubility; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013997:Time Factors; D014018:Tissue Distribution
C504897:12-(3-adamantan-1-ylureido)dodecanoic acid; D004791:Enzyme Inhibitors; D007850:Lauric Acids; D004851:Epoxide Hydrolases; D000218:Adamantane