2. Academic Validation
  3. Structure-Based Optimization of Moracin M as Potent and Selective PDE4 Inhibitors with Antipsoriasis Effects

Structure-Based Optimization of Moracin M as Potent and Selective PDE4 Inhibitors with Antipsoriasis Effects

  • J Med Chem. 2025 Mar 27;68(6):6789-6803. doi: 10.1021/acs.jmedchem.5c00266.
Furong Zhang 1 2,  Tiansheng Zheng 1,  Xue Wang 1,  Yu Chen 1,  Feng Zhang 1,  Xingfu Liu 1,  Sen Wang 1,  Guofeng Yang 1,  Shenghong Xie 1,  Qi Wu 1,  Chao Xu 1,  Qian Zhou 1,  Deyan Wu 1,  Hai-Bin Luo 1 3,  Yi-You Huang 1
Affiliations

Affiliations

  • 1 Key Laboratory of Tropical Biological Resources of Ministry of Education and Hainan Engineering Research Center for Drug Screening and Evaluation, School of Pharmaceutical Sciences, Hainan University, Haikou 570228, China.
  • 2 School of Life and Health Science, Hainan University, Haikou 570228, China.
  • 3 Song Li' Academician Workstation of Hainan University (School of Pharmaceutical Sciences), Yazhou Bay, Sanya 572000, China.
PMID: 40066994 DOI: 10.1021/acs.jmedchem.5c00266
Abstract

Psoriasis is a complex chronic inflammatory disease that severely affects the quality of life of patients. However, current medications could only control the symptoms but not cure psoriasis with unmet medical needs. Herein, structure-based optimizations of natural product moracin M (IC50 of 2.9 μM) led to a novel PDE4 Inhibitor L30 with greatly improved potency (IC50 of 8.6 nM) and remarkable selectivity across Other PDEs families (>201-fold). The binding pattern of L30 with PDE4 revealed by cocrystal structure was different from that of roflumilast. Besides, L30 could effectively inhibit the release of inflammatory cytokines and chemokines in Raw264.7 and HaCaT cell lines. Furthermore, topical administration of L30 exhibited significant therapeutic effects in an imiquimod-induced psoriasis mouse model. These findings highlighted the potential of PDE4 Inhibitor L30 as a novel lead for the treatment of psoriasis.

Figures
Products