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Solid-phase Synthesis of [4.4] Spirocyclic Oximes
Published on: February 6, 2019
Discovery of Novel Isoxazole-Based FXR Agonists Containing a 1,2,4-Oxadiazol-5(4H)-one Ring
Mingliang Liu1,2, Jingjing Shi2, Yi Zang2
1Xuzhou Vocational College of Bioengineering, Xuzhou 221006, China.
Abstract:
Farnesoid X receptor (FXR) is a member of the ″metabolic″ subfamily of nuclear receptors and is mainly present in the liver and intestines, playing a crucial role in bile acid homeostasis, inflammation, and fibrosis. Activation of FXR has emerged as a promising therapeutic strategy for treating metabolic dysfunction-associated steatohepatitis (MASH) or other FXR-dependent diseases. Here, we report our work on the discovery of a series of isoxazole-based FXR agonists containing an oxadiazolone ring. 40 compounds were designed and synthesized based on scaffold hopping and bioisostere strategies. In particular, compound 34 (Linafexor) is a potent FXR agonist with favorable pharmacokinetic properties, high liver distribution, and ideal in vivo efficacy. It has completed Phase II clinical trial for patients with MASH and is currently undergoing a Phase III clinical trial for patients with primary biliary cholangitis (PBC). This article discusses the synthesis and biological properties of this type of new molecules.
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