ABSTRACT
Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) functions as a key regulator in inflammation and cell death and is involved in mediating a variety of inflammatory or degenerative diseases. A number of allosteric RIPK1 inhibitors (RIPK1i) have been developed, and some of them have already advanced into clinical evaluation. Recently, selective RIPK1i that interact with both the allosteric pocket and the ATP-binding site of RIPK1 have started to emerge. Here, we report the rational development of a new series of type-II RIPK1i based on the rediscovery of a reported but mechanistically atypical RIPK3i. We also describe the structure-guided lead optimization of a potent, selective, and orally bioavailable RIPK1i, 62, which exhibits extraordinary efficacies in mouse models of acute or chronic inflammatory diseases. Collectively, 62 provides a useful tool for evaluating RIPK1 in animal disease models and a promising lead for further drug development.
ABSTRACT
ObjectiveTo investigate the influence of olsalazine on tumor necrosis factor-alpha (TNF-α) and interleukin-10 (IL-10) in patients with chronic ulcerative colitis.MethodsSixty patients with chronic ulcerative colitis(observation group),including 22 chronic recurrent cases and 38 chronic persistent cases,were enrolled and treated with olsalazine.Meanwhile,60 healthy volunteers without disease history of ulcerative colitis were selected as control group.The concentrations of TNF- α and IL-10 in serum of the two groups were detected by ELISA and compared.ResultsBefore treatment,the concentration of TNF- α in serum of the observation group was significantly higher than that of control group [ (57.2 ± 10.1 )ng/L vs.(27.2 ± 6.9) ng/L],while IL-10 was significantly lower than that of control group[ (9.2 ± 2.1 ) ng/L vs.(17.3 ±2.9) ng/L] (P ＜0.05).Before treatment,the concentration of TNF-α in serum in chronic persistent patients and chronic recurrent patients[ (56.9 ± 9.9),(57.3 ± 9.7) ng/L ] were significantly higher than that in control group,and serum IL-10 in chronic persistent patients and chronic recurrent patients [ (9.1 ± 2.3 ),(8.4 ± 2.5 ) ng/L ] was significantly lower than that in control group (P＜ 0.05 ).The concentration of TNF- α in serum in observation group after treatment was obviously lower than that before treatment [(28.1 ±8.9) ng/L vs.(57.2 ± 10.1 ) ng/L],and IL-10 was obviously higher than that before treatment [(13.4 ± 10.7) ng/L vs.(9.2 ±2.1 )ng/L] (P ＜ 0.05).The concentration of serum TNF-αand IL-10 in chronic persistent and chronic recurrent patients before and after treatment had statistical significance (P＜0.05 ).ConclusionsOlsalazine can significantly decrease the concentration of TNF- α and increase the concentration of IL-10 in serum in patients with chronic ulcerative colitis.It is worthy of application in clinic.