SAR Studies of N-[2-(1H-Tetrazol-5-yl)phenyl]benzamide Derivatives as Potent G Protein-Coupled Receptor-35 Agonists,ACS Medicinal Chemistry Letters

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SAR Studies of N-[2-(1H-Tetrazol-5-yl)phenyl]benzamide Derivatives as Potent G Protein-Coupled Receptor-35 Agonists
ACS Medicinal Chemistry Letters ( IF 3.5 ) Pub Date : 2018-04-09 00:00:00 , DOI: 10.1021/acsmedchemlett.7b00510
Lai Wei _{1,

2} , Tao Hou ₁ , Chang Lu _{1,

2} , Jixia Wang ₁ , Xiuli Zhang _{1,

3} , Ye Fang ₄ , Yaopeng Zhao ₁ , Jiatao Feng ₁ , Jiaqi Li _{1,

2} , Lala Qu _{1,

2} , Hai-long Piao ₁ , Xinmiao Liang _{1,

3}

Affiliation

G protein-coupled receptor-35 (GPR35) has emerged as a potential target in the treatment of pain and inflammatory and metabolic diseases. We have discovered a series of potent GPR35 agonists based on a coumarin scaffold and found that the introduction of a 1H-tetrazol-5-yl group significantly increased their potency. We designed and synthesized a new series of N-[2-(1H-tetrazol-5-yl)phenyl]benzamide derivatives through a two-step synthetic approach, and characterized their agonistic activities against GPR35 using a dynamic mass redistribution (DMR) assay. N-(5-bromo-2-(1H-tetrazol-5-yl)phenyl)-4-methoxybenzamide (56) and N-(5-bromo-2-(1H-tetrazol-5-yl)phenyl)-2-fluoro-4-methoxybenzamide (63) displayed the highest agonistic potency agonist GPR35 with an EC₅₀ of 0.059 μM and 0.041 μM, respectively. The physicochemical properties of selected compounds were calculated to evaluate their druglikeness, suggesting that compounds 56 and 63 have good druglike properties. Together, N-[2-(1H-tetrazol-5-yl)phenyl]benzamide derivatives are potentially great candidates for developing potent GPR35 agonists.

中文翻译：

N- [2-（1H-替硝唑-5-基）苯基]苯甲酰胺衍生物作为强G蛋白偶联受体35激动剂的SAR研究

G蛋白偶联受体35（GPR35）已成为治疗疼痛，炎性和代谢性疾病的潜在靶标。我们已经发现了一系列基于香豆素骨架的强效GPR35激动剂，并发现引入1 H-四唑-5-基大大提高了它们的效价。我们通过两步合成方法设计和合成了一系列新的N- [2-（1 H-四唑-5-基）苯基]苯甲酰胺衍生物，并使用动态质量重新分配（DMR）表征了它们对GPR35的激动活性。分析。N-（5-溴-2-（1 H-四唑-5-基）苯基）-4-甲氧基苯甲酰胺（56）和N-（5-溴-2-（1 H-四唑-5-基）苯基）-2-氟-4-甲氧基苯甲酰胺（63）显示出最高的激动剂激动剂GPR35，EC _50分别为0.059μM和0.041μM 。计算了所选化合物的理化性质，以评估其药物相似性，表明化合物56和63具有良好的药物相似性能。一起，Ñ - [2-（1H-四唑-5-基）苯基]苯甲酰胺衍生物是潜在地用于开发有效的GPR35激动剂大候选。

更新日期：2018-04-09

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