2. Academic Validation
  3. Discovery of arylbenzylamines as PDE4 inhibitors with potential neuroprotective effect

Discovery of arylbenzylamines as PDE4 inhibitors with potential neuroprotective effect

  • Eur J Med Chem. 2019 Apr 15:168:221-231. doi: 10.1016/j.ejmech.2019.02.026.
Lv Tang 1,  Chang Huang 1,  Jiahong Zhong 1,  JiaPeng He 1,  Jiayin Guo 2,  Menghua Liu 2,  Jiang-Ping Xu 3,  Hai-Tao Wang 1,  Zhong-Zhen Zhou 4
Affiliations

Affiliations

  • 1 Department of Neuropharmacology and Novel Drug Discovery, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, China; Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, China.
  • 2 Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, China.
  • 3 Department of Neuropharmacology and Novel Drug Discovery, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, China; Key Laboratory of Mental Health of the Ministry Education, Southern Medical University, Guangzhou, 510515, China. Electronic address: jpx@smu.edu.cn.
  • 4 Department of Neuropharmacology and Novel Drug Discovery, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, China; Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, China. Electronic address: zhouzz@smu.edu.cn.
PMID: 30822711 DOI: 10.1016/j.ejmech.2019.02.026
Abstract

Growing evidence confirms the potential of PDE4 inhibitors for the treatment of Parkinson's disease. Our reported PDE4 inhibitors FCPR16 and FCPR03 have displayed neuroprotective effects in SH-SY5Y cells, but have very low oral bioavailability. To access analogues with improved bioavailability, a new series of arylbenzylamine derivatives were designed and synthesized. Preliminary screening results of the series showed that arylbenzylamine derivatives bearing a pyridin-3-amine side chain displayed good inhibitory activities against human PDE4B1 and PDE4D7 isoforms. Moreover, kinetic studies revealed that the most potent compounds 11r and 11s with mid-nanomolar IC50 values partially bind to PDE4B1 (Imax = 93% and 90% respectively). Molecular docking results revealed the possible interactions of compounds 11r and 11s with upstream conserved region 2 (UCR2) of PDE4B1, which illuminate possible reasons for their partial inhibition against PDE4. Using a cell-based model of PD, compounds 11r and 11s were found to alleviate cellular Apoptosis in SH-SY5Y cells induced by MPP+ (1-methyl-4-phenylpyridinium), with this neuroprotective effect being greater than PDE4 Inhibitor rolipram. Furthermore, compound 11r displayed nearly sevenfold oral bioavailability (8.20%) than FCPR03 (1.23%).

Keywords

Design; Neuroprotective effect; Parkinson's disease; Phosphodiesterase-4 inhibitors; Synthesis.

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