- The Discovery of Novel ACA Derivatives as Specific TRPM2 Inhibitors that Reduce Ischemic Injury Both in Vitro and in Vivo
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The transient receptor potential melastatin 2 (TRPM2) channel is associated with ischemia/reperfusion injury, inflammation, cancer, and neurodegenerative diseases. However, the limit of specific inhibitors impedes the development of TRPM2-targeted therapeutic agents. To discover more potent and selective TRPM2 inhibitors, 59 N-(p-amylcinnamoyl) anthranilic acid (ACA) derivatives were synthesized and evaluated using calcium imaging and electrophysiology approaches. Systematic structure-activity relationship studies resulted in some potent compounds inhibiting the TRPM2 channel with sub-micromolar half-maximal inhibitory concentration values. Among them, the preferred compound A23 exhibited TRPM2 selectivity over TRPM8 and TRPV1 channels as well as phospholipase A2 and showed neuroprotective activity in vitro. Following pharmacokinetic studies, A23 was further evaluated in a transient middle cerebral artery occlusion model in vivo, which significantly reduced cerebral infarction. These data indicate that A23 might serve as a useful tool for TRPM2-related research as well as a lead compound for the development of therapeutic agents for ischemic injury.
- Zhang, Han,Yu, Peilin,Lin, Hongwei,Jin, Zefang,Zhao, Siqi,Zhang, Yi,Xu, Qingxia,Jin, Hongwei,Liu, Zhenming,Yang, Wei,Zhang, Liangren
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p. 3976 - 3996
(2021/05/04)
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- New potent antagonists of leukotrienes C4 and D4. 1. Synthesis and structure-activity relationships
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(p-Amylcinnamoyl)anthranilic acid (3a) had moderate antagonist activities against LTD4-induced smooth muscle contraction on guinea pig ileum and LTC4-induced bronchoconstriction in anesthetized guinea pigs. Modifications were made in the hydrophobic part (cinnamoyl moiety) and the hydrophilic part (anthranilate moiety) of 3a. A series of 8-(benzoylamino)-2-tetrazol-5-yl-1,4-benzodioxans and 8-(benzoylamino)-2-tetrazol-5-yl-4-oxo-4H-1-benzopyrans were revealed to be potent antagonists of leukotrienes C4 and D4. Among both series, ONO-RS-347 (18k) and ONO-RS411 (19h) were the most potent and orally active antagonists, respectively. Structure-activity relationships are discussed.
- Nakai,Konno,Kosuge,Sakuyama,Toda,Arai,Obata,Katsube,Miyamoto,Okegawa,Kawasaki
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- SYNTHESIS AND SOME TRANSFORMATIONS OF BENZOTHIOPHENE DERIVATIVES
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A number of 3-chloro-2-chlorocarbonylbenzothiophenes with alkyl substituents in various positions of the benzene ring were synthesized by arylation of acrylic acid with the corresponding alkyl-substituted iodobenzenes under the influence of catalytic amounts of palladium acetate and subsequent oxidation of the resulting arylacrylic acids with thionyl chloride.Replacement of the pyridine added in the oxidation reaction by triethylbenzylammonium chloride led to substantial increases in the yields of the desired products.The possibility of conversionof the resulting benzothiophene derivatives to thiophene ring-unsubstituted benzothiophenes was shown in the case of 3-chloro-2-chlorocarbonylbenzothiophene as a result of successive saponification of the 2-chlorocarbonyl group, decarboxylation, and dechlorination.
- Sidorenko, T.N.,Terent'eva, G.A.,Raida, V.S.,Andrienko, O.S.,Savinykh, Yu.V.,Aksenov, V.S.
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p. 1246 - 1250
(2007/10/02)
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