Citation: Deyan Wu, Qingjiang Ma, Yanquan Chen, Guofeng Yang, Fengcai Zhang, Meiyan Jiang, Xue Wang, Xingfu Liu, Qian Zhou, Yi-You Huang, Zhe Li, Hai-Bin Luo. Plasma metabolites-based drug design: Discovery of novel and highly selective phosphodiesterase 5 inhibitors[J]. Chinese Chemical Letters, ;2026, 37(5): 111236. doi: 10.1016/j.cclet.2025.111236 shu

Plasma metabolites-based drug design: Discovery of novel and highly selective phosphodiesterase 5 inhibitors

Deyan Wu ^{a, 1, *,} ,
Qingjiang Ma ^{a, 1} ,
Yanquan Chen ^{b, 1} ,
Guofeng Yang ^a ,
Fengcai Zhang ^b ,
Meiyan Jiang ^b ,
Xue Wang ^a ,
Xingfu Liu ^a ,
Qian Zhou ^a ,
Yi-You Huang ^a ,
Zhe Li ^{b, *,} ,
Hai-Bin Luo ^{a, *,}

a.
Key Laboratory of Tropical Biological Resources of Ministry of Education, School of Pharmaceutical Sciences, Hainan University, Haikou 570228, China
b.
School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China

wudeyan@hainanu.edu.cn

lizhe5@mail.sysu.edu.cn

hbluo@hainanu.edu.cn

Received Date: 17 February 2025
Revised Date: 20 April 2025
Accepted Date: 21 April 2025
Available Online: 22 April 2025

Figures(6)

In drug discovery, it is extremely important to identify highly potent leads with desirable drug-like profiles. Almost all the marketed phosphodiesterase 5 (PDE5) inhibitors such as sildenafil, vardenafil, and tadalafil have poor selectivity over PDE6 or PDE11 and leading to several side effects. Herein, a metabolites-based scaffold hopping strategy was performed to discover selective PDE5 inhibitors with remarkable metabolic stability. The Eu(OTf)₃-catalyzed Mannich-type reaction followed by l-selectride catalyzed reduction was used to prepare chiral 2,3,3a,4,5,6-hexahydro-1H-benzo[b]pyrido[2,3,4-de][1,6] naphthyridines as novel PDE5 inhibitors with high enantioselectivity (> 99% ee and > 30:1 dr). Lead L9 exhibited a half maximal inhibitory concentration (IC₅₀) of 1.03 nmol/L with higher selectivity (> 898-fold) over PDE6 or PDE11 than sildenafil and tadalafil, implying the potential relief from side effects. Especially, the co-crystal binding pattern of L9 with PDE5 is revealed to be different from that of sildenafil, which possibly explain the former's high selectivity. And oral administration of L9·HCl (5.0 mg/kg) exhibited better therapeutic effects than pirfenidone (150 mg/kg) in a bleomycin-induced idiopathic pulmonary fibrosis (IPF) rat model, highlighting the potential of L9·HCl for the treatment of IPF.
- Drug discovery,
- Scaffold hopping,
- High selectivity,
- Phosphodiesterase 5 inhibitors,
- Idiopathic pulmonary fibrosis
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沈阳化工大学材料科学与工程学院沈阳 110142