Design, Synthesis And SAR Study Of 5-trifluoromethylpyridinone Derivatives With High Antifibrotic Activity

Tissue and organ fibrosis are the major causes to disability and death related to a variety of diseases. Currently, approachs for the treatment of fibrotic diseases are very limited. Although there are lots of anti-fibrosis compounds reported, No one were developed in clinical application until the discovery and marketing of Pirfenidone (PFD). PFD is currently the only small molecule drug approved for the treatment of fibrosis. It works on several targets in different stages of fibrosis including TGF-β, IL-1, ICAM, TIMP-1, so on. Fluorofenidone (AKF-PD), a "me-better" drug of PFD, has recently been developed in our group. However, they displayed poor activity and strong first-pass effect, which make them unsuitable for long-term application. Therefore, study on multi-targeting compounds for fibrosis therapy is very promising.Herein, based on the achievements in our previous studies, new series of compounds were designed and synthesized with the purpose of maintaining multi-targeting features and overcoming the drawbacks of fast metabolism. It can be used as leading compounds with excellent pharmacodynamics characters. Furthermore, to find candidates that can be developed as new anti-fibrosis drugs. Additionally, by further investigation on the structure-activity relationship (SAR) and pharmacokinetic properties of certain compounds to obtain valuable information for the optimization of anti-fibrosis drugs with pyridione scaffold and deep understanding about the pathogenesis of fibrotic diseases.In this study, taking PFD as leading compound, two series of pyridione derivatives were designed and synthesized. The structures of the 52 target compounds had been confirmed and the inhibitory activity been preliminary evaluated on NIH3T3 cells by MTT assay with AKF-PD as positive control. The activity results showed that most compounds were more active than AKF-PD, among which 4 compounds were also evaluated in acute toxicity experiments and 2j and 3r showed good drugibility.SAR analysis for benzyl and phenyl pyridine ketones revealed that:1) the existence of trifluoromethyl on C-5 of pyridineone is more favorable for the anti-fibrosis activity; 2) benzyl group is superior to phenyl group on N-1.3) for compounds in both series, there are dramatical increases on the activity for compounds with the linkage of heterocyclic on the aromatic ring.4) For series with benzyl group on N-1, the length of linker between aromatic ring and heterocycle should be three carbon atoms and on p-position of aromatic ring. However, for those with phenyl on N-1, the length should be two carbons.5) For compounds without heterocycle substitutents, the relationship between the length and activity was unobvious.In summary, two series of pyridione derivatives was designed and synthesized and their anti-fibrosis activities were evaluated. SAR of pyridone analogues was firstly reported and two compounds with better drugibility were discovered.What need to be emphasized was that the study provided important information and laid a solid foundation for further research and development of potent multi-target inhibitors for anti-fibrosis.