Abstract
The chemical syntheses and biological evaluation of several potential irreversible inhibitors for prostaglandin (PGH) synthase are described. These inhibitors were modeled after the nonsteroidal antiinflammatory (NSAI) drug phenylbutazone (4-n-butyl-l,2-diphenyl-3,5-pyrazolidinedione). Electrophilic functionalities such as an a-bromo-acetamide, an a-chloroacetamide, a phenylurethane, a propargyl chloride, and several a,j3-unsaturated Michael acceptors were incorporated at the 4-position of the pyrazolidinedione ring structure. None of the derivatives showed evidence of irreversible inhibition of PGH synthase, although several were nearly as potent inhibitors of this enzyme as phenylbutazone. The nitrile obtained from 1,4-conjugate addition of cyanide to one of the unsaturated derivatives was considerably more potent as an inhibitor of PGH synthase than was phenylbutazone.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 563-567 |
| Number of pages | 5 |
| Journal | Journal of Medicinal Chemistry |
| Volume | 30 |
| Issue number | 3 |
| DOIs | |
| State | Published - Mar 1 1987 |
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ASJC Scopus subject areas
- Molecular Medicine
- Drug Discovery
Cite this
Preparation and Evaluation of Electrophilic Derivatives of Phenylbutazone as Inhibitors of Prostaglandin-H Synthase. / Vennerstrom, Jonathan L; Holmes, Thomas J.
In: Journal of Medicinal Chemistry, Vol. 30, No. 3, 01.03.1987, p. 563-567.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Preparation and Evaluation of Electrophilic Derivatives of Phenylbutazone as Inhibitors of Prostaglandin-H Synthase
AU - Vennerstrom, Jonathan L
AU - Holmes, Thomas J.
PY - 1987/3/1
Y1 - 1987/3/1
N2 - The chemical syntheses and biological evaluation of several potential irreversible inhibitors for prostaglandin (PGH) synthase are described. These inhibitors were modeled after the nonsteroidal antiinflammatory (NSAI) drug phenylbutazone (4-n-butyl-l,2-diphenyl-3,5-pyrazolidinedione). Electrophilic functionalities such as an a-bromo-acetamide, an a-chloroacetamide, a phenylurethane, a propargyl chloride, and several a,j3-unsaturated Michael acceptors were incorporated at the 4-position of the pyrazolidinedione ring structure. None of the derivatives showed evidence of irreversible inhibition of PGH synthase, although several were nearly as potent inhibitors of this enzyme as phenylbutazone. The nitrile obtained from 1,4-conjugate addition of cyanide to one of the unsaturated derivatives was considerably more potent as an inhibitor of PGH synthase than was phenylbutazone.
AB - The chemical syntheses and biological evaluation of several potential irreversible inhibitors for prostaglandin (PGH) synthase are described. These inhibitors were modeled after the nonsteroidal antiinflammatory (NSAI) drug phenylbutazone (4-n-butyl-l,2-diphenyl-3,5-pyrazolidinedione). Electrophilic functionalities such as an a-bromo-acetamide, an a-chloroacetamide, a phenylurethane, a propargyl chloride, and several a,j3-unsaturated Michael acceptors were incorporated at the 4-position of the pyrazolidinedione ring structure. None of the derivatives showed evidence of irreversible inhibition of PGH synthase, although several were nearly as potent inhibitors of this enzyme as phenylbutazone. The nitrile obtained from 1,4-conjugate addition of cyanide to one of the unsaturated derivatives was considerably more potent as an inhibitor of PGH synthase than was phenylbutazone.
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U2 - 10.1021/jm00386a020
DO - 10.1021/jm00386a020
M3 - Article
VL - 30
SP - 563
EP - 567
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
SN - 0022-2623
IS - 3
ER -