AGN 190383, a novel phospholipase inhibitor with topical anti-inflammatory activity.
AGN 190383 is a 5-hydroxy-2(5H)-furanone ring analog of the marine natural product manoalide. When applied topically, AGN 190383 inhibits phorbol ester induced mouse ear edema. It is a potent inhibitor of bee venom phospholipase A2 and blocks the release of arachidonic acid from calcium ionophore A23187 stimulated human neutrophils. AGN 190383 also inhibits both hormone-operated and depolarization-dependent calcium mobilization in GH3 cells, as well as fMLP stimulated increases in free cytosolic calcium in human PMNs. Furthermore, it is also able to block the release of the neutral protease elastase from stimulated neutrophils. The effects of AGN 190383 on arachidonic acid metabolism and leukocyte function may account, in part, for its anti-inflammatory activity in vivo.
De Vries
G W
GW
Department of Biological Sciences, Allergan, Inc., Irvine, CA 92715.
Lee
G
G
Amdahl
L
L
Wenzel
M
M
Garst
M
M
Wheeler
L A
LA
D000287:Administration, Topical; D000595:Amino Acid Sequence; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D016718:Arachidonic Acid / Q000378:metabolism; D000001:Calcimycin / Q000494:pharmacology; D005663:Furans / Q000494:pharmacology*; D051379:Mice; D008969:Molecular Sequence Data; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D009504:Neutrophils / Q000187:drug effects / Q000201:enzymology; D010196:Pancreatic Elastase / Q000378:metabolism; D010740:Phospholipases / Q000037:antagonists & inhibitors*; D010741:Phospholipases A / Q000037:antagonists & inhibitors; D054467:Phospholipases A2; D013729:Terpenes / Q000494:pharmacology
D000893:Anti-Inflammatory Agents; D005663:Furans; D013729:Terpenes; C073112:AGN 190383; D016718:Arachidonic Acid; D000001:Calcimycin; D009240:N-Formylmethionine Leucyl-Phenylalanine; C045673:manoalide; D010740:Phospholipases; D010741:Phospholipases A; D054467:Phospholipases A2; D010196:Pancreatic Elastase