Synthesis and Biological Evaluation of Peripheral 5HT2A Antagonists for Nonalcoholic Fatty Liver Disease

Abstract

Non-alcoholic Fatty Liver Disease (NAFLD), characterized by excessive fat accumulation in the liver in the absence of alcohol consumption, is a growing epidemic worldwide. Recent findings suggest that the peripheral roles of serotonin (5-hydroxytryptamine, 5HT) were found to regulate energy homeostasis. More specifically, 5HT2A is known to regulate hepatic lipid metabolism and high-fat diet (HFD)-fed liver-specific 5HT2A knockout (5HT2A LKO) mice exhibited a reduction in hepatic lipid accumulation and hepatic triglyceride (TG). Part 1. A new series of pimavanserin (a 5HT2A inverse agonist and antagonist FDA approved for Parkinson’s disease psychosis in 2016) derivatives were designed and synthesized with the aim to develop peripherally acting 5HT2A antagonists. Among the synthesized compounds, glutamate derivative 14a and amino alcohol derivative 37b exhibited good in vitro activity with an IC50 value of 8.4 and 0.02 nM, respectively. Compounds 14a and 37b showed limited blood-brain barrier (BBB) penetration. In addition, compounds 14a and 37b selectively inhibited 5HT2A toward 5HT subtypes. HFD-fed 14a-treated mice showed a reduction in liver weight and hepatic lipid accumulation. In addition, 5HT2A is known to regulate cancer proliferation in colorectal cancer, confirming the anti-tumor activity of compound 37b. Tumor weight and volume decreased in 37b-treated mice in HCT-116 xenograft model. Part 2. Compound 48b, a hit compound which contains a tyrosine moiety, identified by in-house library screening was chosen for further structural modification. A series of tyrosine derivatives were designed and synthesized to obtain potent 5HT2A antagonists. Compound 51a showed excellent in vitro activity with an IC50 value of 0.17 nM. Compound 51a also inhibited 5HT2B subtype with an IC50 value of 8.55 nM. Liver steatosis and lobular inflammation were reduced in 51a-treated mice upon HFD feeding.