Discovery of Novel Natural Product-Based PDE4 Inhibitors for Ischemic Stroke Treatment without Emetogenicity at Ultra-High Doses

  • J Med Chem. 2026 Feb 12;69(3):3037-3061. doi: 10.1021/acs.jmedchem.5c02951.
Chuang Xia  1  2 ,  Mingjia Yu  3 ,  Yujie Ni  1 ,  Shanfang Fang  1 ,  Kaiwen Feng  1 ,  Tingting Zhang  1 ,  Chunping Gu  4 ,  Kaibin Huang  3 ,  Zhong-Zhen Zhou  1
Affiliations
  • 1. Innovation Program of Drug Research on Neurological and Metabolic Diseases, Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China.
  • 2. Evaluation & Inspection Center of GDMPA, Guangzhou 510080, China.
  • 3. Department of Neurology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.
  • 4. Department of Pharmacy, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.
PMID: 41615772 DOI: 10.1021/acs.jmedchem.5c02951
Abstract

Phosphodiesterase-4 (PDE4) inhibitors show potential for treating ischemic stroke, but are often constrained by emesis or low blood-brain barrier (BBB) permeability. To overcome these challenges, this paper developed novel PDE4 inhibitors via AI-driven structural evolution of natural antistroke products and identified the Phthalide derivative B05 as a PDE4 Inhibitor exhibiting excellent selectivity (selectivity index > 420), favorable pharmacological properties (F = 15.5%), and good BBB permeability. Significantly, B05 did not induce vomiting at ultrahigh doses (60 mg/kg), a significant advantage over conventional PDE4 inhibitors. B05 protected neuronal cells from oxygen-glucose deprivation and reoxygenation-induced injury. Additionally, in the middle cerebral artery occlusion and reperfusion model, B05 significantly reduced infarct volume, preserved BBB integrity, attenuated cerebral edema, inhibited astrocyte and microglial activation, prevented ischemia-induced neuronal Apoptosis, and improved poststroke motor function and cognitive performance. These findings support the potential of B05 as a promising candidate for the treatment of ischemic stroke.

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