- Highly specific and broadly potent inhibitors of mammalian secreted phospholipases A2
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We report a series of inhibitors of secreted phospholipases A2 (sPLA2s) based on substituted indoles, 6,7-benzoindoles, and indolizines derived from LY315920, a well-known indole-based sPLA2 inhibitor. Using the human group X sPLA2 crystal structure, we prepared a highly potent and selective indole-based inhibitor of this enzyme. Also, we report human and mouse group IIA and IIE specific inhibitors and a substituted 6,7-benzoindole that inhibits nearly all human and mouse sPLA 2s in the low nanomolar range.
- Oslund, Rob C.,Cermak, Nathan,Gelb, Michael H.
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supporting information; experimental part
p. 4708 - 4714
(2009/06/06)
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- Indolizine SPLA2inhibitors
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A class of novel indolizine-1-functional compounds and indolizine-3-functional compounds is disclosed together with the use of such indolizine compounds for inhibiting sPLA2mediated release of fatty acids for treatment of conditions such as septic shock. The compounds are indolizine-1-acetamides, indolizine-1-acetic acid hydrazides, indolizine-1-glyoxylamides, indolizine-3-acetamides, indolizine-3-acetic acid hydraxides, and indolizine-3-glyoxylasides.
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Page/Page column 63
(2010/11/30)
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- Potent inhibitors of secretory phospholipase A2: Synthesis and inhibitory activities of indolizine and indene derivatives
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Phospholipase A2 is an enzyme which hydrolyzes the sn-2 position of certain cellular phospholipids. The liberated lysophospholipid and arachidonic acid are precursors in the biosynthesis of various biologically active products. As human nonpancreatic sPLA2 is present in high levels in the blood of patients in several pathological conditions, the potent sPLA2 inhibitors have been suggested to be useful drugs. Here we describe the synthesis, structure-activity relationship, and inhibitory activities of indolizine and indene derivatives. 1-(Carbamoylmethyl)indolizine derivatives and 1-oxamoylindolizine derivatives exhibited very potent inhibitory activity. The former was unstable to air oxidation, but the latter exhibited an improvement both in stability and in potency. Some compounds approached the stoichiometric limit of the chromogenic assay.
- Hagishita, Sanji,Yamada, Masaaki,Shirahase, Kazuhiro,Okada, Toshihiko,Murakami, Yasushi,Ito, Yuji,Matsuura, Takaharu,Wada, Masaaki,Kato, Toshiyuki,Ueno, Masahiko,Chikazawa, Yukiko,Yamada, Katsutoshi,Ono, Takashi,Teshirogi, Isao,Ohtani, Mitsuaki
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p. 3636 - 3658
(2007/10/03)
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