Design and synthesis of aminothiazole modulators of the gamma-secretase enzyme

Rynearson Kevin D.; Buckle Ronald N.; Barnes Keith D.; Herr R. Jason; Mayhew Nicholas J.; Paquette William D.; Sakwa Samuel A.; Nguyen Phuong D.; Johnson Graham; Tanzi Rudolph E.; Wagner Steven L.

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Design and synthesis of aminothiazole modulators of the gamma-secretase enzyme

机译：γ-分泌酶的氨基噻唑调节剂的设计与合成

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The design and construction of a series of novel aminothiazole-derived gamma-secretase modulators is described. The incorporation of heterocyclic replacements of the terminal phenyl D-ring of lead compound 1 was conducted in order to align potency with favorable drug-like properties. gamma-Secretase modulator 28 displayed good activity for in vitro inhibition of A beta 42, as well as substantial improvement in ADME and physicochemical properties, including aqueous solubility. Pharmacokinetic evaluation of compound 28 in mice revealed good brain penetration, as well as good clearance, half-life, and volume of distribution which collectively support the continued development of this class of compounds. (C) 2016 Published by Elsevier Ltd.

机译：描述了一系列新颖的氨基噻唑衍生的γ-分泌酶调节剂的设计和构建。进行铅化合物1的末端苯基D-环的杂环取代基的掺入，以使效力与有利的类药物性质对准。 γ-分泌酶调节剂28表现出良好的体外抑制Aβ42活性，以及ADME和理化特性（包括水溶性）的显着改善。化合物28在小鼠中的药代动力学评估显示，其良好的大脑渗透能力以及良好的清除率，半衰期和分布体积共同支持了这类化合物的持续开发。（C）2016由Elsevier Ltd.出版

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《Bioorganic and Medicinal Chemistry Letters》 |2016年第16期|共10页
作者
Rynearson Kevin D.; Buckle Ronald N.; Barnes Keith D.; Herr R. Jason; Mayhew Nicholas J.; Paquette William D.; Sakwa Samuel A.; Nguyen Phuong D.; Johnson Graham; Tanzi Rudolph E.; Wagner Steven L.;
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正文语种 eng
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Alzheimer's disease; gamma-Secretase modulators; Aminothiazoles;

机译：阿尔茨海默氏病;γ-分泌酶调节剂;氨基噻唑;

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1. Design and synthesis of aminothiazole modulators of the gamma-secretase enzyme [J] . Rynearson Kevin D., Buckle Ronald N., Barnes Keith D., Bioorganic and Medicinal Chemistry Letters . 2016,第16期

机译：γ-分泌酶的氨基噻唑调节剂的设计与合成
2. Design and synthesis of a novel series of cyanoindole derivatives as potent gamma-secretase modulators [J] . Bischoff Francois P., Velter Adriana Ingrid, Minne Garrett, Bioorganic and Medicinal Chemistry Letters . 2019,第14期

机译：一种新型氰基吲哚衍生物系列的设计与合成有效的γ-分泌酶调节剂
3. Design and synthesis of piperazine derivatives as a novel class of gamma-secretase modulators that selectively lower A beta(42) production [J] . Takai Takafumi, Koike Tatsuki, Honda Eiji, Bioorganic and medicinal chemistry . 2015,第9期

机译：设计和合成哌嗪衍生物，作为一类新型的γ-分泌酶调节剂，可选择性降低A beta（42）的产生
4. Design, Synthesis, and Cytoprotective Effect of 2-Aminothiazole Analogues as Potent Poly(ADP-Ribose) Polymerase-1 Inhibitors [C] . Wen-Ting Zhang, Gang-Ying Chen, Yi-Jing Zhu, ICMSI;International conference of molecular simulations and applied informatics technologies . 2010

机译：2-氨基噻唑类似物作为强力聚（ADP-核糖）聚合酶-1抑制剂的设计，合成和细胞保护作用
5. Design, synthesis and screening of a 2-aminothiazole library for inhibition of nucleotide-diphospho-sugar utilizing enzymes. [D] . Phillips, John Hudson. 2005

机译：设计，合成和筛选2-氨基噻唑文库，用于利用酶抑制核苷酸二磷酸糖。
6. Multifunctional Isosteric Pyridine Analogs-Based 2-Aminothiazole: Design Synthesis and Potential Phosphodiesterase-5 Inhibitory Activity [O] . Abdel Haleem M. Hussein, Ahmed A. Khames, Abu-Bakr A. El-Adasy, 2021

机译：基于多功能旁边吡啶类似物的2-氨基噻唑：设计合成和潜在的磷酸二酯酶-5抑制活性
7. Multifunctional Isosteric Pyridine Analogs-Based 2-Aminothiazole: Design, Synthesis, and Potential Phosphodiesterase-5 Inhibitory Activity [O] . Abdel Haleem M. Hussein, Ahmed A. Khames, Abu-Bakr A. El-Adasy, 2021

机译：基于多功能旁边吡啶类似物的2-氨基噻唑：设计，合成和潜在的磷酸二酯酶-5抑制活性

Design and synthesis of aminothiazole modulators of the gamma-secretase enzyme

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