2. Academic Validation
  3. Discovery of A20 with 4-(2-methoxyphenyl)-1H-pyrazole scaffold as a potent and selective ROCK2 inhibitor

Discovery of A20 with 4-(2-methoxyphenyl)-1H-pyrazole scaffold as a potent and selective ROCK2 inhibitor

  • Bioorg Med Chem Lett. 2025 Dec 15:129:130391. doi: 10.1016/j.bmcl.2025.130391.
Junzheng Wang 1,  Bin Peng 1,  Guodong Liang 1,  Yan Zhao 2,  Xin Gao 1,  Yuting Zhao 1,  Lu Ga 1,  Ruijuan Li 3,  Yuheng Ma 4
Affiliations

Affiliations

  • 1 Key Laboratory for Candidate Medicine Design and Screening Based on Chemical Biology, College of Pharmacy, Inner Mongolia Medical University, Hohhot, PR China.
  • 2 Key Laboratory for Candidate Medicine Design and Screening Based on Chemical Biology, College of Pharmacy, Inner Mongolia Medical University, Hohhot, PR China. Electronic address: zhaoyan@immu.edu.cn.
  • 3 Key Laboratory for Candidate Medicine Design and Screening Based on Chemical Biology, College of Pharmacy, Inner Mongolia Medical University, Hohhot, PR China. Electronic address: 20150172@immu.edu.cn.
  • 4 Key Laboratory for Candidate Medicine Design and Screening Based on Chemical Biology, College of Pharmacy, Inner Mongolia Medical University, Hohhot, PR China. Electronic address: 20120311@immu.edu.cn.
PMID: 40886899 DOI: 10.1016/j.bmcl.2025.130391
Abstract

Rho-associated protein kinase 2 (ROCK2) has become a promising therapeutic target for diseases such as neurological disorders and fibrosis. In this study, structural optimization based on the binding mode of lead compound M214 and ROCK2 was conducted and compound A20 with a 4-(2-methoxyphenyl)-1H-pyrazole scaffold exhibited superior inhibitory activity against ROCK2 with IC50 value of 0.18 μM and inhibited ROCK1 with IC50 value of 3.0 μM. Molecular docking study showed that hydrogen bond interactions between pyrazole ring of A20 and Met172 and Glu170 of ROCK2 played key roles in enhancing inhibitory activity.

Keywords

Molecular docking; ROCK2 inhibitor; Structure-activity relationship; Synthesis.

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