Potent Inhibitors of Secretory Phospholipase A2: Synthesis and Inhibitory Activities of Indolizine and Indene Derivatives
| Autor: | Masahiko Ueno, Takashi Ono, Masaaki Yamada, Toshihiko Okada, Yasushi Murakami, Toshiyuki Kato, Yukiko Chikazawa, Yuji Ito, Mitsuaki Ohtani, Sanji Hagishita, Isao Teshirogi, Takaharu Matsuura, Katsutoshi Yamada, Masaaki Wada, Kazuhiro Shirahase |
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| Rok vydání: | 1996 |
| Předmět: |
Alkylation
Stereochemistry Hydroxylation Methylation Chemical synthesis Phospholipases A Structure-Activity Relationship chemistry.chemical_compound Phospholipase A2 Drug Discovery Humans Structure–activity relationship Enzyme Inhibitors Indene Molecular Structure biology Indolizines Biological activity Phospholipases A2 Indenes chemistry Biochemistry Enzyme inhibitor biology.protein Molecular Medicine Indolizine Arachidonic acid Oxidation-Reduction |
| Zdroj: | Journal of Medicinal Chemistry. 39:3636-3658 |
| ISSN: | 1520-4804 0022-2623 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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