Improving metabolic stability with deuterium: The discovery of GPU-028, a potent free fatty acid receptor 4 agonists. Issue 24 (15th December 2017)

• Record Type: Journal Article
• Authors: Li, Zheng; Xu, Xue; Li, Gang; Fu, Xiaoting; Liu, Yanzhi; Feng, Yufeng; Wang, Mingyan; Ouyang, Yunting; Han, Jing
• Is Part Of: Bioorganic & medicinal chemistry. Volume 25:Issue 24(2017)
• Page Start: 6647
• Page End: 6652
• Publication Date: 2017-12-15
• Subjects: Deuterium -- FFA4 agonist -- GPR120 -- TUG-891 -- Type 2 diabetes; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2017.10.040
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Abstract: The free fatty acid receptor 4 (FFA4) has emerged as a promising anti-diabetic target due to its function in improvement of insulin secretion and insulin resistance. The FFA4 agonist TUG-891 revealed great potential as a widely used pharmacological tool, but it has been suffered from high plasma clearance probably because the phenylpropanoic acid is vulnerable to β-oxidation. To identify metabolically stable analog without influence on physiological mechanism of TUG-891, we tried to incorporate deuterium at the α-position of phenylpropionic acid to afford compound4 (GPU-028). As expected, GPU-028 revealed a longer half-life ( T 1/2 = 1.66 h), lower clearance (CL = 0.97 L/h/kg) and higher maximum plasma concentration ( C max = 2035.23 μg/L), resulting in a 4-fold higher exposure than TUG-891. Although GPU-028 exhibited a similar agonistic activity in comparison to TUG-891, the hypoglycemic effect of GPU-028 was better than that of TUG-891 after treatment over four weeks in diet-induced obese mice. These positive results indicated that GPU-028 might be a better pharmacological tool than TUG-891 to explore physiological function of FFA4, especially on the in vivo study.