Prostaglandin-H Synthase Inhibition by Malonamides. Ring-Opened Analogues of Phenylbutazone

Jonathan L Vennerstrom, Thomas J. Holmes

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

Recent reports of serious concern regarding the safe clinical use of phenylbutazone and its hydroxylated metabolite (oxyphenbutazone) as antiinflammatory agents have prompted the further investigation of ring-opened (malonamide) derivatives as potentially preferable therapeutic derivatives. Earlier reports have claimed reduced toxicity among similar derivatives. These studies reveal the relative degree of prostaglandin-H (PGH) synthase inhibitory activity among a series of malonamide derivatives. Contrary to observations in the pyrazolidinedione series, incorporation of a nonpolar butyl side chain in these malonamides was not beneficial but, rather, detrimental to enzyme-inhibitory activity. Although none of the reported nonbutylated malonamides was as potent an inhibitor of this enzyme as phenylbutazone, they all showed some inhibitory activity. PGH synthase inhibitory activity was especially pronounced in the bis(p-hydroxy anilide) derivatives, even extending to succinamide and adipamide derivatives. of some interest is the observation that all of these p-hydroxy anilide derivatives were more potent inhibitors of this enzyme than acetaminophen.

Original languageEnglish (US)
Pages (from-to)434-437
Number of pages4
JournalJournal of Medicinal Chemistry
Volume30
Issue number2
DOIs
StatePublished - Feb 1 1987
Externally publishedYes

Fingerprint

Phenylbutazone
Prostaglandin-Endoperoxide Synthases
Anilides
Enzyme Inhibitors
Oxyphenbutazone
Acetaminophen
Anti-Inflammatory Agents
malonamide
Enzymes
Therapeutics

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

Prostaglandin-H Synthase Inhibition by Malonamides. Ring-Opened Analogues of Phenylbutazone. / Vennerstrom, Jonathan L; Holmes, Thomas J.

In: Journal of Medicinal Chemistry, Vol. 30, No. 2, 01.02.1987, p. 434-437.

Research output: Contribution to journalArticle

@article{fd1847f07f0141638c9e635d8c2af3f8,
title = "Prostaglandin-H Synthase Inhibition by Malonamides. Ring-Opened Analogues of Phenylbutazone",
abstract = "Recent reports of serious concern regarding the safe clinical use of phenylbutazone and its hydroxylated metabolite (oxyphenbutazone) as antiinflammatory agents have prompted the further investigation of ring-opened (malonamide) derivatives as potentially preferable therapeutic derivatives. Earlier reports have claimed reduced toxicity among similar derivatives. These studies reveal the relative degree of prostaglandin-H (PGH) synthase inhibitory activity among a series of malonamide derivatives. Contrary to observations in the pyrazolidinedione series, incorporation of a nonpolar butyl side chain in these malonamides was not beneficial but, rather, detrimental to enzyme-inhibitory activity. Although none of the reported nonbutylated malonamides was as potent an inhibitor of this enzyme as phenylbutazone, they all showed some inhibitory activity. PGH synthase inhibitory activity was especially pronounced in the bis(p-hydroxy anilide) derivatives, even extending to succinamide and adipamide derivatives. of some interest is the observation that all of these p-hydroxy anilide derivatives were more potent inhibitors of this enzyme than acetaminophen.",
author = "Vennerstrom, {Jonathan L} and Holmes, {Thomas J.}",
year = "1987",
month = "2",
day = "1",
doi = "10.1021/jm00385a031",
language = "English (US)",
volume = "30",
pages = "434--437",
journal = "Journal of Medicinal Chemistry",
issn = "0022-2623",
publisher = "American Chemical Society",
number = "2",

}

TY - JOUR

T1 - Prostaglandin-H Synthase Inhibition by Malonamides. Ring-Opened Analogues of Phenylbutazone

AU - Vennerstrom, Jonathan L

AU - Holmes, Thomas J.

PY - 1987/2/1

Y1 - 1987/2/1

N2 - Recent reports of serious concern regarding the safe clinical use of phenylbutazone and its hydroxylated metabolite (oxyphenbutazone) as antiinflammatory agents have prompted the further investigation of ring-opened (malonamide) derivatives as potentially preferable therapeutic derivatives. Earlier reports have claimed reduced toxicity among similar derivatives. These studies reveal the relative degree of prostaglandin-H (PGH) synthase inhibitory activity among a series of malonamide derivatives. Contrary to observations in the pyrazolidinedione series, incorporation of a nonpolar butyl side chain in these malonamides was not beneficial but, rather, detrimental to enzyme-inhibitory activity. Although none of the reported nonbutylated malonamides was as potent an inhibitor of this enzyme as phenylbutazone, they all showed some inhibitory activity. PGH synthase inhibitory activity was especially pronounced in the bis(p-hydroxy anilide) derivatives, even extending to succinamide and adipamide derivatives. of some interest is the observation that all of these p-hydroxy anilide derivatives were more potent inhibitors of this enzyme than acetaminophen.

AB - Recent reports of serious concern regarding the safe clinical use of phenylbutazone and its hydroxylated metabolite (oxyphenbutazone) as antiinflammatory agents have prompted the further investigation of ring-opened (malonamide) derivatives as potentially preferable therapeutic derivatives. Earlier reports have claimed reduced toxicity among similar derivatives. These studies reveal the relative degree of prostaglandin-H (PGH) synthase inhibitory activity among a series of malonamide derivatives. Contrary to observations in the pyrazolidinedione series, incorporation of a nonpolar butyl side chain in these malonamides was not beneficial but, rather, detrimental to enzyme-inhibitory activity. Although none of the reported nonbutylated malonamides was as potent an inhibitor of this enzyme as phenylbutazone, they all showed some inhibitory activity. PGH synthase inhibitory activity was especially pronounced in the bis(p-hydroxy anilide) derivatives, even extending to succinamide and adipamide derivatives. of some interest is the observation that all of these p-hydroxy anilide derivatives were more potent inhibitors of this enzyme than acetaminophen.

UR - http://www.scopus.com/inward/record.url?scp=0023152238&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0023152238&partnerID=8YFLogxK

U2 - 10.1021/jm00385a031

DO - 10.1021/jm00385a031

M3 - Article

VL - 30

SP - 434

EP - 437

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

IS - 2

ER -