Optimization of potent, selective and orally bioavailable biphenyl scaffold as FABP4 inhibitors for anti-inflammation

Yulong He; Shunyi Li; Yueyue Zhu; Yujie Wang; Yuqi Chen; Deqiang Zhang; Heyao Wang; Yingxia Li

doi:10.1016/j.ejmech.2023.115319

Optimization of potent, selective and orally bioavailable biphenyl scaffold as FABP4 inhibitors for anti-inflammation

Eur J Med Chem. 2023 May 5:253:115319. doi: 10.1016/j.ejmech.2023.115319. Epub 2023 Apr 5.

Authors

Yulong He¹, Shunyi Li², Yueyue Zhu¹, Yujie Wang¹, Yuqi Chen¹, Deqiang Zhang², Heyao Wang³, Yingxia Li⁴

Affiliations

¹ School of Pharmacy, Fudan University, Shanghai, 201203, China.
² Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China; University of Chinese Academy of Sciences, Beijing, 100049, China.
³ Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China; University of Chinese Academy of Sciences, Beijing, 100049, China. Electronic address: hywang@simm.ac.cn.
⁴ School of Pharmacy, Fudan University, Shanghai, 201203, China. Electronic address: liyx417@fudan.edu.cn.

PMID: 37037141
DOI: 10.1016/j.ejmech.2023.115319

Abstract

Fatty-acid binding protein 4 (FABP4) is an essential driver for the progression of metabolic-related inflammatory diseases including obesity, diabetes, atherosclerosis, and various lipid metabolism-related tumors. However, FABP4 inhibitors are not yet available for clinical use, which may be associated with their poor selectivity of FABP3, unsatisfactory efficacy and physicochemical properties. Herein, we reported a systematic optimization of a class of biphenyl scaffold molecules as potent FABP4 inhibitors. Further in vitro and in vivo pharmacokinetic studies identified a selective and orally bioavailable compound 10g, with K_i of 0.51 μM against FABP4, K_i of 33.01 μM against FABP3 and bioavailability F% value of 89.4%. In vivo anti-inflammatory efficacy and multi-organ protection study in LPS-induced inflammatory mice model highlighted the potential of compound 10g as a therapeutic candidate in inflammation-related diseases.

Keywords: Anti-inflammation; Biphenyl scaffold; FABP4 inhibitor; Oral bioavailability; Selectivity; Structure–activity relationship.

MeSH terms

Animals
Anti-Inflammatory Agents / metabolism
Anti-Inflammatory Agents / pharmacology
Anti-Inflammatory Agents / therapeutic use
Biphenyl Compounds* / pharmacology
Fatty Acid-Binding Proteins*
Mice

Substances

diphenyl
Fatty Acid-Binding Proteins
Biphenyl Compounds
Anti-Inflammatory Agents
Fabp4 protein, mouse