Design of bioavailable derivatives of 12-(3-adamantan-1-yl-ureido)dodecanoic acid, a potent inhibitor of the soluble epoxide hydrolase

In Hae Kim, Kosuke Nishi, Hsing Ju Tsai, Tanya Bradford, Yasuko Koda, Takaho Watanabe, Christophe Morisseau, Joanne Blanchfield, Istvan Toth, Bruce D. Hammock

Research output: Contribution to journalArticle

45 Citations (Scopus)

Abstract

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 °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.

Original languageEnglish (US)
Pages (from-to)312-323
Number of pages12
JournalBioorganic and Medicinal Chemistry
Volume15
Issue number1
DOIs
StatePublished - Jan 1 2007

Fingerprint

Epoxide Hydrolases
Solubility
Freezing
Derivatives
Melting point
Pharmacokinetics
Physical properties
Oils
Esters
Pressure regulation
Acids
Esterification
Blood pressure
Metabolism
Amides
Functional groups
Biological Availability
Blood Vessels
Animals
Triglycerides

Keywords

  • 1,3-disubstituted ureas
  • Pharmacokinetic properties
  • sEH inhibitors
  • Soluble epoxide hydrolase (sEH)

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Organic Chemistry
  • Drug Discovery
  • Pharmaceutical Science

Cite this

Design of bioavailable derivatives of 12-(3-adamantan-1-yl-ureido)dodecanoic acid, a potent inhibitor of the soluble epoxide hydrolase. / Kim, In Hae; Nishi, Kosuke; Tsai, Hsing Ju; Bradford, Tanya; Koda, Yasuko; Watanabe, Takaho; Morisseau, Christophe; Blanchfield, Joanne; Toth, Istvan; Hammock, Bruce D.

In: Bioorganic and Medicinal Chemistry, Vol. 15, No. 1, 01.01.2007, p. 312-323.

Research output: Contribution to journalArticle

Kim, IH, Nishi, K, Tsai, HJ, Bradford, T, Koda, Y, Watanabe, T, Morisseau, C, Blanchfield, J, Toth, I & Hammock, BD 2007, 'Design of bioavailable derivatives of 12-(3-adamantan-1-yl-ureido)dodecanoic acid, a potent inhibitor of the soluble epoxide hydrolase', Bioorganic and Medicinal Chemistry, vol. 15, no. 1, pp. 312-323. https://doi.org/10.1016/j.bmc.2006.09.057
Kim, In Hae ; Nishi, Kosuke ; Tsai, Hsing Ju ; Bradford, Tanya ; Koda, Yasuko ; Watanabe, Takaho ; Morisseau, Christophe ; Blanchfield, Joanne ; Toth, Istvan ; Hammock, Bruce D. / Design of bioavailable derivatives of 12-(3-adamantan-1-yl-ureido)dodecanoic acid, a potent inhibitor of the soluble epoxide hydrolase. In: Bioorganic and Medicinal Chemistry. 2007 ; Vol. 15, No. 1. pp. 312-323.
@article{847090f9346d45f593792ae0fd9321da,
title = "Design of bioavailable derivatives of 12-(3-adamantan-1-yl-ureido)dodecanoic acid, a potent inhibitor of the soluble epoxide hydrolase",
abstract = "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 °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.",
keywords = "1,3-disubstituted ureas, Pharmacokinetic properties, sEH inhibitors, Soluble epoxide hydrolase (sEH)",
author = "Kim, {In Hae} and Kosuke Nishi and Tsai, {Hsing Ju} and Tanya Bradford and Yasuko Koda and Takaho Watanabe and Christophe Morisseau and Joanne Blanchfield and Istvan Toth and Hammock, {Bruce D.}",
year = "2007",
month = "1",
day = "1",
doi = "10.1016/j.bmc.2006.09.057",
language = "English (US)",
volume = "15",
pages = "312--323",
journal = "Bioorganic and Medicinal Chemistry",
issn = "0968-0896",
publisher = "Elsevier Limited",
number = "1",

}

TY - JOUR

T1 - Design of bioavailable derivatives of 12-(3-adamantan-1-yl-ureido)dodecanoic acid, a potent inhibitor of the soluble epoxide hydrolase

AU - Kim, In Hae

AU - Nishi, Kosuke

AU - Tsai, Hsing Ju

AU - Bradford, Tanya

AU - Koda, Yasuko

AU - Watanabe, Takaho

AU - Morisseau, Christophe

AU - Blanchfield, Joanne

AU - Toth, Istvan

AU - Hammock, Bruce D.

PY - 2007/1/1

Y1 - 2007/1/1

N2 - 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 °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.

AB - 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 °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.

KW - 1,3-disubstituted ureas

KW - Pharmacokinetic properties

KW - sEH inhibitors

KW - Soluble epoxide hydrolase (sEH)

UR - http://www.scopus.com/inward/record.url?scp=33750949953&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=33750949953&partnerID=8YFLogxK

U2 - 10.1016/j.bmc.2006.09.057

DO - 10.1016/j.bmc.2006.09.057

M3 - Article

C2 - 17046265

AN - SCOPUS:33750949953

VL - 15

SP - 312

EP - 323

JO - Bioorganic and Medicinal Chemistry

JF - Bioorganic and Medicinal Chemistry

SN - 0968-0896

IS - 1

ER -