Pyrrolidine inhibitors of human cytosolic phospholipase A2. Part 2 : Synthesis of potent and crystallized 4-triphenylmethylthio derivative 'pyrrophenone'

We synthesized a potent and crystallized human cytosolic phospholipase A2alpha inhibitor, pyrrophenone (6) which inhibits the isolated enzyme with an IC50 value of 4.2 nM. Pyrrophenone shows potent inhibition of arachidonic acid release, prostaglandin E2, thromboxane B2, and leukotriene B4 formation...

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Published in:Bioorganic & medicinal chemistry letters 2001-02, Vol.11 (4), p.587-590
Main Authors: SENO, Kaoru, OKUNO, Takayuki, NISHI, Koichi, MURAKAMI, Yasushi, YAMADA, Katsutoshi, NAKAMOTO, Shozo, ONO, Takashi
Format: Article
Language:English
Subjects:
Arachidonic Acid - metabolism
Biological and medical sciences
Bones, joints and connective tissue. Antiinflammatory agents
Crystallization
Cytosol - enzymology
Dinoprostone - biosynthesis
Enzyme Inhibitors - chemical synthesis
Enzyme Inhibitors - pharmacology
Humans
Medical sciences
Pharmacology. Drug treatments
Phospholipases A - antagonists & inhibitors
Phospholipases A2
Pyrrolidines - chemical synthesis
Pyrrolidines - pharmacology
Thromboxane B2 - biosynthesis
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Summary:We synthesized a potent and crystallized human cytosolic phospholipase A2alpha inhibitor, pyrrophenone (6) which inhibits the isolated enzyme with an IC50 value of 4.2 nM. Pyrrophenone shows potent inhibition of arachidonic acid release, prostaglandin E2, thromboxane B2, and leukotriene B4 formation in human whole blood. The magnitudes of prostaglandin E2 and thromboxane B2 inhibition are the same as those of indomethacin.
ISSN:0960-894X
1464-3405
DOI:10.1016/S0960-894X(01)00003-8