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

Lai Wei; Tao Hou; Chang Lu; Jixia Wang; Xiuli Zhang; Ye Fang; Yaopeng Zhao; Jiatao Feng; Jiaqi Li; Lala Qu; Hai-Long Piao; Xinmiao Liang

doi:10.1021/acsmedchemlett.7b00510

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

ACS Med Chem Lett. 2018 Apr 9;9(5):422-427. doi: 10.1021/acsmedchemlett.7b00510. eCollection 2018 May 10.

Authors

Lai Wei^{1

2}, Tao Hou¹, Chang Lu^{1

2}, Jixia Wang¹, Xiuli Zhang^{1

3}, Ye Fang⁴, Yaopeng Zhao¹, Jiatao Feng¹, Jiaqi Li^{1

2}, Lala Qu^{1

2}, Hai-Long Piao¹, Xinmiao Liang^{1

3}

Affiliations

¹ Key Lab of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China.
² University of Chinese Academy of Sciences, Beijing, 100049, China.
³ Co-innovation Center of Neuroregeneration, Nantong University, Nantong 226019, China.
⁴ Biochemical Technologies, Science and Technology Division, Corning, New York 14831, United States.

Abstract

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.