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Fragment Based Optimization of Metabotropic Glutamate Receptor 2 (mGluR2) Positive Allosteric Modulators in the Absence of Structural Information
Journal of Medicinal Chemistry ( IF 7.3 ) Pub Date : 2018-03-05 00:00:00 , DOI: 10.1021/acs.jmedchem.8b00161
György Szabó 1 , György I. Túrós 1 , Sándor Kolok 1 , Mónika Vastag 1 , Zsuzsanna Sánta 1 , Miklós Dékány 1 , György I. Lévay 1 , István Greiner 1 , Minami Natsumi 2 , Watanabe Tatsuya 2 , György M. Keserű 3
Affiliation  

Metabotropic glutamate receptor 2 (mGluR2) positive allosteric modulators (PAMs) have been implicated as potential pharmacotherapy for psychiatric conditions. Screening our corporate compound deck, we identified a benzotriazole fragment (4) that was rapidly optimized to a potent and metabolically stable early lead (16). The highly lipophilic character of 16, together with its limited solubility, permeability, and high protein binding, however, did not allow reaching of the proof of concept in vivo. Since further attempts on the optimization of druglike properties were unsuccessful, the original hit 4 has been revisited and was optimized following the principles of fragment based drug discovery (FBDD). Lacking structural information on the receptor–ligand complex, we implemented a group efficiency (GE) based strategy and identified a new fragment like lead (60) with more balanced profile. Significant improvement achieved on the druglike properties nominated the compound for in vivo proof of concept studies that revealed the chemotype being a promising PAM lead targeting mGluR2 receptors.

中文翻译:

在缺乏结构信息的情况下基于片段的代谢型谷氨酸受体2(mGluR2)正变构调节剂的优化。

代谢型谷氨酸受体2(mGluR2)阳性变构调节剂(PAMs)已被认为是治疗精神疾病的潜在药物。筛选我们的公司复合甲板后,我们确定了苯并三唑片段(4),该片段被快速优化为有效且代谢稳定的早期铅(16)。然而,16的高度亲脂性及其有限的溶解性,通透性和高蛋白结合性,无法在体内达到概念验证的目的。由于进一步优化药物样性质的尝试均未成功,因此原始命中4已重新审视并根据基于片段的药物发现(FBDD)原理进行了优化。缺乏关于受体-配体复合物的结构信息,我们实施了基于群效率(GE)的策略,并确定了一个新的片段,如铅(60)具有更平衡的轮廓。该化合物的类药性取得了显着改善,提名该化合物用于体内概念验证研究,该研究显示化学型是靶向mGluR2受体的有希望的PAM铅。
更新日期:2018-03-05
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