Discovery of indoline-based derivatives as effective ROCK2 inhibitors for the potential new treatment of idiopathic pulmonary fibrosis.

Suhong Fu, Yi Wen, Bin Peng, Minghai Tang, Mingsong Shi, Jiang Liu, Yingxue Yang, Wenting Si, Yong Guo, Xiandeng Li, Tingting Yan, Jie Kang, Heying Pei, Lijuan Chen

Bioorganic chemistry 2023 Aug

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Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and devastating lung disease with a median survival of only 3-5 years. Due to the lack of effective therapy, IPF threatens human health. Recently, increasing reports have indicated that Rho-associated coiled-coil protein kinases (ROCKs) play important roles in the development of IPF and might represent a novel target for the treatment of IPF. Herein, a new series of selective ROCK2 inhibitors based on indoline were designed and synthesized. Structural modification resulted in optimized compound 9b with an IC50 value of 6 nM against ROCK2 and the inhibition of collagen gel contraction. Cellular assays demonstrated that 9b could significantly suppress the expression of collagen I and α-SMA, and inhibited ROCK signaling pathway. Oral administration of compound 9b (10 mg/kg) exerted more significant anti-pulmonary fibrosis effects than nintedanib (100 mg/kg) and KD025 (100 mg/kg) in a bleomycin-induced IPF rat model, suggesting that 9b could serve as a potential lead compound for the treatment of IPF. Copyright © 2023. Published by Elsevier Inc.

Citation

Suhong Fu, Yi Wen, Bin Peng, Minghai Tang, Mingsong Shi, Jiang Liu, Yingxue Yang, Wenting Si, Yong Guo, Xiandeng Li, Tingting Yan, Jie Kang, Heying Pei, Lijuan Chen. Discovery of indoline-based derivatives as effective ROCK2 inhibitors for the potential new treatment of idiopathic pulmonary fibrosis. Bioorganic chemistry. 2023 Aug;137:106539