Indole Inhibitors of Human Nonpancreatic Secretory Phospholipase A₂. 3. Indole-3-glyoxamides

Abstract

The preceding papers of this series detail the development of functionalized indole-3-acetamides as inhibitors of hnps-PLA2. We describe here the extension of the structure-activity relationship to include a series of indole-3-glyoxamide derivatives. Functionalized indole-3-glyoxamides with an acidic substituent appended to the 4- or 5-position of the indole ring were prepared and tested as inhibitors of hnps-PLA2. It was found that the indole-3-glyoxamides with a 4-oxyacetic acid substituent had optimal inhibitory activity. These inhibitors exhibited an improvement in potency over the best of the indole-3-acetamides, and LY315920 (6m) was selected for evaluation clinically as an hnps-PLA2 inhibitor.

Effect of a Selective Inhibitor of Secretory Phospholipase A2, S-5920/LY315920Na, on Experimental Acute Pancreatitis in Rats

“…Several protease inhibitors have been developed to treat acute pancreatitis, but there was no low molecular inhibitor of lipolytic enzymes such as PLA 2 until the discovery of S-5920 / LY315920Na (18). In the present study, the systemic administration of this novel sPLA 2 inhibitor showed apparent efficacy against the severe hemorrhagic necrotizing acute pancreatitis induced by the intraductal injection of porcine pancreatic sPLA 2 -IB plus taurocholate.…”

“…Indeed, when combined with bile acid and injected into the pancreatic duct, this enzyme causes various degrees of acute pancreatitis in animals depending on its dose (16). Although the IC 50 value of S-5920 / LY315920 for sPLA 2 -IB is 20-to 90-fold higher than that for sPLA 2 -IIA (18), sPLA 2 -IB should be also inhibited by this compound when the concentration of this compound in plasma is high enough. Thus, we evaluated the effect of S-5920/ LY315920Na on the lipolytic enzyme-related severe acute pancreatitis in rats to find whether an sPLA 2 inhibitor could show beneficial effects against mortality and biochemical and histological changes arising from the development of pancreatitis.…”

“…Its median inhibitory concentration (IC 50 ) values for human non-pancreatic sPLA 2 -IIA, human pancreatic sPLA 2 -IB, and porcine pancreatic sPLA 2 -IB were 0.009, 0.228, and 0.048 mM, respectively (18). It also inhibits rat nonpancreatic sPLA 2 -IIA and pancreatic sPLA 2 -IB with IC 50 values of 0.002 and 0.027 mM, respectively (13).…”

Synthesis of New Heterocycles Derived from 3-(3-Methyl-1H-indol-2-yl)-3-oxopropanenitrile as Potent Antifungal Agents

“…1 Indole derivatives have been reported to exhibit antifungal, 2-7 antibacterial, [2][3][4]8,9 antiphage, 2 antiproliferative, 10 optimal inhibitory, 11 anticholinergic, 12 antiviral, 13 antitumor, 14 antiinflammatory, 15 and antihypertensive 16 activities and also as plant growth regulators. 17 In view of the above mentioned findings and as continuation of our efforts in the synthesis of new biologically active heterocycles, [18][19][20][21][22] we report herein the synthesis of some new heterocycles with the indole moieties.…”

The First Potent Inhibitor of Mammalian Group X Secreted Phospholipase A2: Elucidation of Sites for Enhanced Binding

“…[12][13][14][15][16] Workers at Lilly Labs and Shionogi & Co. Ltd. have reported on substituted indoles, exemplified by compound I, as potent inhibitors of group IIA sPLA 2 ( Figure 1). [12][13][14][15] Among the various reported inhibitors of sPLA 2 ,17 these compounds appear to be the most potent and also appear to have the most drug-like properties. With the discovery of additional sPLA 2 enzymes, we have been interested in exploring these indole analogues as inhibitors of all of the members of the sPLA 2 enzyme class.…”