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 in human whole blood. The magnitudes of prostaglandin E2 and thromboxane B2 inhibition are the same as those of indomethacin.
Shionogi Research Laboratories, Shionogi & Co., Ltd., Osaka, Japan. kaoru.seno@shionogi.co.jp
K
K
Seno
T
T
Okuno
K
K
Nishi
Y
Y
Murakami
K
K
Yamada
S
S
Nakamoto
T
T
Ono
D016718:Arachidonic Acid / Q000378:metabolism; D003460:Crystallization; D003600:Cytosol / Q000201:enzymology; D015232:Dinoprostone / Q000096:biosynthesis; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D006801:Humans; D010741:Phospholipases A / Q000037:antagonists & inhibitors*; D054467:Phospholipases A2; D011759:Pyrrolidines / Q000138:chemical synthesis* / Q000494:pharmacology; D013929:Thromboxane B2 / Q000096:biosynthesis
D004791:Enzyme Inhibitors; D011759:Pyrrolidines; D016718:Arachidonic Acid; D013929:Thromboxane B2; D010741:Phospholipases A; D054467:Phospholipases A2; D015232:Dinoprostone