New candidate compounds against silver filings discovered by the research group of Ye Chun, Liu Hong and Tang Wei of Shanghai Institute of medicine, Chinese Academy of Sciences

Recently, Xu Yechun research group, Liu Hong research group and Tang Wei research group of Shanghai Pharmaceutical Research Institute of Chinese Academy of Sciences published a cover article entitled "structure aided identification and optimization of tetrahydroisoquinolines as new PDE4 inhibitors leading to discovery of an effective antibiotics agent" in Journal of medical chemistry The team found a new skeleton PDE4 selective inhibitor, oral and external use can effectively improve the skin symptoms of psoriasis model mice, and some evaluation indicators are better than the market drug apremilast Psoriasis is an immune-mediated chronic recurrent skin inflammation, which is intractable and hard to treat, and seriously affects the quality of life and physical and mental health of patients It is one of the important problems to be solved in the field of dermatology With the increasing pressure of modern life, the incidence rate of the disease has increased year by year in China Although the existing drugs have been used in the treatment of psoriasis, they still can not meet the clinical needs It is urgent to find new targets and develop new drugs Phosphodiesterase 4 (PDE4) is mainly expressed in neutrophils, eosinophils, monocytes and other immune cells It plays an important role in the regulation of inflammation and is an effective drug target for the treatment of inflammatory diseases At present, PDE4 inhibitors are mainly used to treat inflammatory and immune diseases such as psoriatic arthritis and chronic obstructive pulmonary disease Apremillast, a small molecule inhibitor of PDE4, was approved by the FDA in 2014 as a drug for the treatment of plaque psoriasis and psoriatic arthritis, indicating that PDE4 can be used as an effective target for the development of new safe, effective and affordable small molecule anti psoriasis drugs The team found that the structure of berberine, the natural product, contains the classical pharmacophore (catechol group) of PDE4 inhibitor, and berberine has anti-inflammatory effect Based on the constructed berberine derivative compound library, we found the compound 2 with high inhibition activity to PDE4D by means of molecular docking, enzyme activity test and crystal structure analysis of the complex In order to further clarify the structure-activity relationship of compound 2 inhibiting PDE4D, a series of fragment molecules and analogues were designed and synthesized by the researchers It was found that the tail indole ring plays an important role in maintaining the activity through the determination of enzyme activity inhibition rate, thermodynamic binding parameters and crystal structure of several complexes, and the optimal linker between the mother nucleus of tetrahydroisoquinoline and indole ring was determined Subsequently, through structural optimization and combining cell-based functional activity data and preliminary pharmacokinetic research results, the team will select compound 16 for animal efficacy evaluation In acute inflammatory mice, oral administration of compound 16 significantly reduced the expression of inflammatory factors In the mice model of psoriasis induced by imiquimod, both oral and external compound 16 can significantly improve the symptoms of psoriasis At present, based on this type of skeleton, the team has obtained candidate compounds with better biological activity at the molecular and cellular level and better efficacy in psoriasis model animals Systematic preclinical evaluation research is in progress Researcher Xu Yechun, researcher Liu Hong and researcher Tang Wei of Shanghai Pharmaceutical Research Institute are the co authors of this paper Dr Zhang Xianglei of Xu Yechun research group, master student Dong Guangyu of Liu Hong research group and Dr Li Heng of Tang Wei research group are the co authors The research was supported by the strategic leading science and technology program of the Chinese Academy of Sciences and the national key R & D plan Local administration of compound 16 effectively alleviated the skin lesions of mice with psoriasis induced by imiquimod (source: J Med Chem.)