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

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.

 

Comments:

The passage describes a study focused on the development of potential treatments for idiopathic pulmonary fibrosis (IPF), a progressive lung disease with a poor prognosis. The researchers designed and synthesized a new series of selective inhibitors for Rho-associated coiled-coil protein kinases (ROCKs), which are believed to play a role in the development of IPF.

Among the compounds tested, compound 9b showed the most promising results. It exhibited a high inhibitory potency against ROCK2, with an IC50 value of 6 nM, and effectively reduced collagen gel contraction, a characteristic feature of IPF. In cellular assays, compound 9b significantly suppressed the expression of collagen I and α-smooth muscle actin (α-SMA), both of which are associated with lung fibrosis. Additionally, it inhibited the ROCK signaling pathway, which further supports its potential therapeutic effect.

To evaluate the efficacy in vivo, the researchers conducted experiments in a rat model of bleomycin-induced IPF. Oral administration of compound 9b at a dose of 10 mg/kg demonstrated superior anti-pulmonary fibrosis effects compared to two reference drugs, nintedanib (at 100 mg/kg) and KD025 (at 100 mg/kg). These findings suggest that compound 9b could be a promising lead compound for the treatment of IPF.

It's important to note that the information provided is a summary of a hypothetical research study and does not represent any real-world findings. The passage uses scientific language and terminology typically found in scientific papers.

Related Products

Cat.No.	Product Name	Information
S7936	Belumosudil (KD025)	Belumosudil (KD025, SLx-2119) is an orally available, and selective ROCK2 inhibitor with IC50 and Ki of 60 nM and 41 nM, respectively. Phase 2.

Related Targets

ROCK