苯并噻吩衍生物作为磷酸二酯酶 10A（PDE10A）抑制剂：从命中到先导的研究。
Benzothiophene derivatives as phosphodiesterase 10A (PDE10A) inhibitors: Hit-to-lead studies.
机构信息
Asubio Pharma Co., Ltd., 6-4-3 Minatojima-Minamimachi, Chuo-ku, Kobe, Hyogo 650-0047, Japan.
Asubio Pharma Co., Ltd., 6-4-3 Minatojima-Minamimachi, Chuo-ku, Kobe, Hyogo 650-0047, Japan.
出版信息
Bioorg Med Chem Lett. 2019 Jun 1;29(11):1419-1422. doi: 10.1016/j.bmcl.2019.03.021. Epub 2019 Mar 19.
A novel series of benzothiophene derivatives was discovered as phosphodiesterase 10A (PDE10A) inhibitors. Structure-activity relationship studies on high-throughput screening hit compound 1 led to the identification of 7-acetyl-3-methyl-N-(quinolin-2-yl)-1-benzothiophene-2-carboxamide (16), with potent inhibitory activity (PDE10A IC = 7.6 nM) and selectivity (>1300-fold selectivity over the other tested phosphodiesterases). In addition, a novel methyl-induced conformational alteration of the benzothiophene-2-carboxamide derivatives is reported.
我们发现了一系列新的苯并噻吩衍生物，它们可作为磷酸二酯酶 10A（PDE10A）抑制剂。对高通量筛选命中化合物 1 的结构-活性关系研究导致鉴定出 7-乙酰基-3-甲基-N-(喹啉-2-基)-1-苯并噻吩-2-甲酰胺（16），其具有很强的抑制活性（PDE10A IC = 7.6 nM）和选择性（对其他测试的磷酸二酯酶的选择性 > 1300 倍）。此外，还报道了苯并噻吩-2-甲酰胺衍生物中一种新的甲基诱导的构象改变。
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