Design, synthesis and biological evaluation of novel pyrrolo[2,3-d]pyrimidine derivatives as cathepsin L inhibitor for the treatment of acute lung injury.

Acute lung injury (ALI), a frequent complication among sepsis patients in intensive care units (ICU), is a serious public health problem due to its high mortality rate and the lack of effective treatments in clinic. Cathepsin L (CTSL), which contributes to inflammation, has been demonstrated as a promising therapeutic target for the treatment of ALI. Herein, a series of pyrrolo[2,3-d]pyrimidine derivatives were designed and synthesized. The leading compound 6a showed a high anti-inflammatory activity, achieving inhibition rates of 65 % for IL-6 and 70 % for IL-8 in LPS-stimulated human bronchial epithelial (HBE) cells at a concentration of 5 μM without significant cytotoxicity. Besides, compound 6a successfully suppressed CSTL activity by directly binding to CSTL, and exhibited a good kinase selectivity on CTSL over CTSB, CTSC, CTSS, CTSH and other inflammation-related kinases. The NF-κB and p38 signaling pathways, which lie downstream of CTSL, were also blocked by compound 6a in LPS-treated cells. Moreover, compound 6a significantly alleviates LPS-induced ALI in mice through its anti-inflammatory effects. In conclusion, compound 6a serves as a selective CTSL inhibitor with prominent anti-inflammatory activities and a potential therapeutic agent for the treatment of ALI.