Substituted 2-Acylaminocycloalkylthiophene-3-carboxylic Acid Arylamides as Inhibitors of the Calcium-Activated Chloride Channel Transmembrane Protein 16A (TMEM16A)

Truong Eric C.; Phuan Puay W.; Reggi Amanda L.; Ferrera Loretta; Galietta Luis J. V.; Levy Sarah E.; Moises Alannah C.; Ca Onur; Diez-Cecilia Elena; Lee Sujin; Verlanan Alan S.; Anderson Marc O.

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Substituted 2-Acylaminocycloalkylthiophene-3-carboxylic Acid Arylamides as Inhibitors of the Calcium-Activated Chloride Channel Transmembrane Protein 16A (TMEM16A)

机译：取代的2-酰氨环环烷基硫戊烯-3-羧酸芳基胺作为钙激活氯通道跨膜蛋白16a的抑制剂（tmem16a）

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Transmembrane protein 16A (TMEM16A), also called anoctamin 1 (ANO1), is a calcium-activated chloride channel expressed widely mammalian cells, including epithelia, vascular smooth muscle tissue, electrically excitable cells, and some tumors. TMEM16A inhibitors have been proposed for treatment of disorders of epithelial fluid and mucus secretion, hypertension, asthma, and possibly cancer. Herein we report, by screening, the discovery of 2-acylaminocycloalkylthiophene-3-carboxylic acid arylamides (AACTs) as inhibitors of TMEM16A and analysis of 48 synthesized analogs (10ab-10bw) of the original AACT compound (10aa). Structure activity studies indicated the importance of benzene substituted as 2- or 4-methyl, or 4-fluoro, and defined the significance of thiophene substituents and size of the cycloalkylthiophene core. The most potent compound (10bm), which contains an unusual bromodifluoroacetamide at the thiophene 2-position, had IC50 of similar to 30 nM, similar to 3.6-fold more potent than the most potent previously reported TMEM16A inhibitor 4 (Ani9), and >10-fold improved metabolic stability. Direct and reversible inhibition of TMEM16A by 10bm was demonstrated by patch-clamp analysis. AACTs may be useful as pharmacological tools to study TMEM16A function and as potential drug development candidates.

机译：跨膜蛋白16A（TMEM16A），也称为Anoctamin 1（AnO1），是钙激活的氯化物通道，表达广泛的哺乳动物细胞，包括上皮细胞，血管平滑肌组织，电激发细胞和一些肿瘤。已经提出了TMEM16A抑制剂用于治疗上皮液和粘液分泌，高血压，哮喘和可能癌症的疾病。在此，通过筛选来报告2-酰氨基环烷烯-3-羧酸芳基胺-3-羧酸芳基酰胺（ACT）作为TMEM16a的抑制剂和48个合成的类似物（10ab-10bw）的原始AACT化合物（10aa）的分析。结构活性研究表明，苯取代为2-或4-甲基，或4-氟，并限定了噻吩取代基的意义和环烷基噻吩核的尺寸。最有效的化合物（10bm），其含有在噻吩2-位置的不寻常的溴二氟乙酰胺，其具有与30nm相似的IC50，类似于比以前报告的TMEM16A抑制剂4（ANI9）的最有效的3.6倍。 10倍改善的代谢稳定性。通过Patch-Clamp分析证明了通过10Bm的直接和可逆抑制TMEM16A。 AACTS可用作研究TMEM16A功能和潜在的药物开发候选者的药理学工具。

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《Journal of Medicinal Chemistry》 |2017年第11期|共10页
作者
Truong Eric C.; Phuan Puay W.; Reggi Amanda L.; Ferrera Loretta; Galietta Luis J. V.; Levy Sarah E.; Moises Alannah C.; Ca Onur; Diez-Cecilia Elena; Lee Sujin; Verlanan Alan S.; Anderson Marc O.;
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作者单位

San Francisco State Univ Dept Chem &

Biochem San Francisco CA 94132 USA;

Univ Calif San Francisco Dept Med San Francisco CA 94143 USA;

San Francisco State Univ Dept Chem &

Biochem San Francisco CA 94132 USA;

Ist Giannina Gaslini UOC Genet Med I-16148 Genoa Italy;

Telethon Inst Genet &

Med TIGEM I-80078 Pozzuoli NA Italy;

San Francisco State Univ Dept Chem &

Biochem San Francisco CA 94132 USA;

San Francisco State Univ Dept Chem &

Biochem San Francisco CA 94132 USA;

Univ Calif San Francisco Dept Med San Francisco CA 94143 USA;

San Francisco State Univ Dept Chem &

Biochem San Francisco CA 94132 USA;

Univ Calif San Francisco Dept Med San Francisco CA 94143 USA;

Univ Calif San Francisco Dept Med San Francisco CA 94143 USA;

San Francisco State Univ Dept Chem &

Biochem San Francisco CA 94132 USA;

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正文语种 eng
中图分类药学;
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1. Substituted 2-Acylaminocycloalkylthiophene-3-carboxylic Acid Arylamides as Inhibitors of the Calcium-Activated Chloride Channel Transmembrane Protein 16A (TMEM16A) [J] . Truong Eric C., Phuan Puay W., Reggi Amanda L., Journal of Medicinal Chemistry . 2017,第11期

机译：取代的2-酰氨环环烷基硫戊烯-3-羧酸芳基胺作为钙激活氯通道跨膜蛋白16a的抑制剂（tmem16a）
2. The Sixth Transmembrane Segment Is a Major Gating Component of the TMEM16A Calcium-Activated Chloride Channel [J] . Peters Christian J., Gilchrist John M., Tien Jason, Neuron . 2018,第5期

机译：第六跨膜段是TMEM16A钙活化氯化物通道的主要浇注组分
3. Phosphatidylinositol 4,5-bisphosphate, cholesterol, and fatty acids modulate the calcium-activated chloride channel TMEM16A (ANO1) [J] . De Jesus-Perez Jose J., Cruz-Rangel Silvia, Espino-Saldana Angeles E., Biochimica et Biophysica Acta. Molecular and cell biology of Lipids . 2018,第3期

机译：磷脂酰肌醇4,5-双磷酸酯，胆固醇和脂肪酸调节钙活化氯通道TMEM16A（ANO1）
4. Expression Clone of TMEM16A as a Calcium-Activated Chloride Channels in CHO Cells [C] . Feng Hao, Yiju Hou, Chen Zhao, ICASET 2013 . 2013

机译：TMEM16a的表达克隆作为CHO细胞中的钙激活氯化物通道
5. Calcium-activated chloride channels (CaCCs) regulate action potential and synaptic responses in hippocampal pyramidal neurons. [D] . Huang, Wendy C. 2010

机译：钙激活的氯离子通道（CaCC）调节海马锥体神经元的动作电位和突触反应。
6. Substituted 2-acylamino-cycloalkylthiophene-3-carboxylic acid arylamides as inhibitors of the calcium-activated chloride channel transmembrane protein 16A (TMEM16A) [O] . Eric C. Truong, Puay W. Phuan, Amanda L. Reggi, -1

机译：取代的2-酰基氨基-环烷基噻吩-3-羧酸芳基酰胺作为钙激活的氯离子通道膜蛋白16A（TMEM16A）的抑制剂
7. Inhibition of transmembrane member 16A calcium-activated chloride channels by natural flavonoids contributes to flavonoid anticancer effects [O] . Xuan Zhang, Honglin Li, Huiran Zhang, 2017

机译：通过天然类黄酮酸抑制跨膜构件16a钙活化氯化物通道有助于黄酮类化抗癌作用

Substituted 2-Acylaminocycloalkylthiophene-3-carboxylic Acid Arylamides as Inhibitors of the Calcium-Activated Chloride Channel Transmembrane Protein 16A (TMEM16A)

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