Preparation and evaluation of electrophilic derivatives of phenylbutazone as inhibitors of prostaglandin-H synthase.
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-1,2-diphenyl-3,5-pyrazolidinedione). Electrophilic functionalities such as an alpha-bromoacetamide, an alpha-chloroacetamide, a phenylurethane, a propargyl chloride, and several alpha,beta-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.
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis*; D016861:Cyclooxygenase Inhibitors; D007202:Indicators and Reagents; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D013058:Mass Spectrometry; D008861:Microsomes / Q000201:enzymology; D010653:Phenylbutazone / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000494:pharmacology; D012669:Seminal Vesicles / Q000201:enzymology; D012756:Sheep; D013329:Structure-Activity Relationship
D000894:Anti-Inflammatory Agents, Non-Steroidal; D016861:Cyclooxygenase Inhibitors; D007202:Indicators and Reagents; D010653:Phenylbutazone