Synthesis and structure-activity relationship studies of urea-containing pyrazoles as dual inhibitors of cyclooxygenase-2 and soluble epoxide hydrolase

Sung Hee Hwang, Karen M. Wagner, Christophe Morisseau, Jun Yan Liu, Hua Dong, Aaron T. Wecksler, Bruce D. Hammock

Research output: Contribution to journalArticle

88 Citations (Scopus)

Abstract

A series of dual inhibitors containing a 1,5-diarylpyrazole and a urea were designed, synthesized, and evaluated as novel COX-2/sEH dual inhibitors in vitro using recombinant enzyme assays and in vivo using a lipopolysaccharide (LPS) induced model of pain in rats. The best inhibition potencies and selectivity for sEH and COX-2 over COX-1 were obtained with compounds (21b, 21i, and 21j) in which both the 1,5-diaryl-pyrazole group and the urea group are linked with a three-methylene group. Compound 21i showed the best pharmacokinetic profiles in both mice and rats (higher AUC and longer half-life). Following subcutaneous administration at 10 mg/kg, compound 21i exhibited antiallodynic activity that is more effective than the same dose of either a COX-2 inhibitor (celecoxib) or a sEH inhibitor (t-AUCB) alone, as well as coadministration of both inhibitors. Thus, these novel dual inhibitors exhibited enhanced in vivo antiallodynic activity in a nociceptive behavioral assay.

Original languageEnglish (US)
Pages (from-to)3037-3050
Number of pages14
JournalJournal of Medicinal Chemistry
Volume54
Issue number8
DOIs
StatePublished - Apr 28 2011

Fingerprint

Pyrazoles
Epoxide Hydrolases
Cyclooxygenase 2 Inhibitors
Celecoxib
Structure-Activity Relationship
Urea
Enzyme Assays
Area Under Curve
Half-Life
Lipopolysaccharides
Pharmacokinetics
Pain

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

Synthesis and structure-activity relationship studies of urea-containing pyrazoles as dual inhibitors of cyclooxygenase-2 and soluble epoxide hydrolase. / Hwang, Sung Hee; Wagner, Karen M.; Morisseau, Christophe; Liu, Jun Yan; Dong, Hua; Wecksler, Aaron T.; Hammock, Bruce D.

In: Journal of Medicinal Chemistry, Vol. 54, No. 8, 28.04.2011, p. 3037-3050.

Research output: Contribution to journalArticle

Hwang, Sung Hee ; Wagner, Karen M. ; Morisseau, Christophe ; Liu, Jun Yan ; Dong, Hua ; Wecksler, Aaron T. ; Hammock, Bruce D. / Synthesis and structure-activity relationship studies of urea-containing pyrazoles as dual inhibitors of cyclooxygenase-2 and soluble epoxide hydrolase. In: Journal of Medicinal Chemistry. 2011 ; Vol. 54, No. 8. pp. 3037-3050.
@article{75f28f680ab448a69fe9e0221049fdbe,
title = "Synthesis and structure-activity relationship studies of urea-containing pyrazoles as dual inhibitors of cyclooxygenase-2 and soluble epoxide hydrolase",
abstract = "A series of dual inhibitors containing a 1,5-diarylpyrazole and a urea were designed, synthesized, and evaluated as novel COX-2/sEH dual inhibitors in vitro using recombinant enzyme assays and in vivo using a lipopolysaccharide (LPS) induced model of pain in rats. The best inhibition potencies and selectivity for sEH and COX-2 over COX-1 were obtained with compounds (21b, 21i, and 21j) in which both the 1,5-diaryl-pyrazole group and the urea group are linked with a three-methylene group. Compound 21i showed the best pharmacokinetic profiles in both mice and rats (higher AUC and longer half-life). Following subcutaneous administration at 10 mg/kg, compound 21i exhibited antiallodynic activity that is more effective than the same dose of either a COX-2 inhibitor (celecoxib) or a sEH inhibitor (t-AUCB) alone, as well as coadministration of both inhibitors. Thus, these novel dual inhibitors exhibited enhanced in vivo antiallodynic activity in a nociceptive behavioral assay.",
author = "Hwang, {Sung Hee} and Wagner, {Karen M.} and Christophe Morisseau and Liu, {Jun Yan} and Hua Dong and Wecksler, {Aaron T.} and Hammock, {Bruce D.}",
year = "2011",
month = "4",
day = "28",
doi = "10.1021/jm2001376",
language = "English (US)",
volume = "54",
pages = "3037--3050",
journal = "Journal of Medicinal Chemistry",
issn = "0022-2623",
publisher = "American Chemical Society",
number = "8",

}

TY - JOUR

T1 - Synthesis and structure-activity relationship studies of urea-containing pyrazoles as dual inhibitors of cyclooxygenase-2 and soluble epoxide hydrolase

AU - Hwang, Sung Hee

AU - Wagner, Karen M.

AU - Morisseau, Christophe

AU - Liu, Jun Yan

AU - Dong, Hua

AU - Wecksler, Aaron T.

AU - Hammock, Bruce D.

PY - 2011/4/28

Y1 - 2011/4/28

N2 - A series of dual inhibitors containing a 1,5-diarylpyrazole and a urea were designed, synthesized, and evaluated as novel COX-2/sEH dual inhibitors in vitro using recombinant enzyme assays and in vivo using a lipopolysaccharide (LPS) induced model of pain in rats. The best inhibition potencies and selectivity for sEH and COX-2 over COX-1 were obtained with compounds (21b, 21i, and 21j) in which both the 1,5-diaryl-pyrazole group and the urea group are linked with a three-methylene group. Compound 21i showed the best pharmacokinetic profiles in both mice and rats (higher AUC and longer half-life). Following subcutaneous administration at 10 mg/kg, compound 21i exhibited antiallodynic activity that is more effective than the same dose of either a COX-2 inhibitor (celecoxib) or a sEH inhibitor (t-AUCB) alone, as well as coadministration of both inhibitors. Thus, these novel dual inhibitors exhibited enhanced in vivo antiallodynic activity in a nociceptive behavioral assay.

AB - A series of dual inhibitors containing a 1,5-diarylpyrazole and a urea were designed, synthesized, and evaluated as novel COX-2/sEH dual inhibitors in vitro using recombinant enzyme assays and in vivo using a lipopolysaccharide (LPS) induced model of pain in rats. The best inhibition potencies and selectivity for sEH and COX-2 over COX-1 were obtained with compounds (21b, 21i, and 21j) in which both the 1,5-diaryl-pyrazole group and the urea group are linked with a three-methylene group. Compound 21i showed the best pharmacokinetic profiles in both mice and rats (higher AUC and longer half-life). Following subcutaneous administration at 10 mg/kg, compound 21i exhibited antiallodynic activity that is more effective than the same dose of either a COX-2 inhibitor (celecoxib) or a sEH inhibitor (t-AUCB) alone, as well as coadministration of both inhibitors. Thus, these novel dual inhibitors exhibited enhanced in vivo antiallodynic activity in a nociceptive behavioral assay.

UR - http://www.scopus.com/inward/record.url?scp=79955428056&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=79955428056&partnerID=8YFLogxK

U2 - 10.1021/jm2001376

DO - 10.1021/jm2001376

M3 - Article

VL - 54

SP - 3037

EP - 3050

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

IS - 8

ER -