Citation: Han Yuan, Fengcai Zhang, Hongzhe Huang, Jiafei Wu, Yi Yang, Wanyi Huang, Dongjing Yang, Zhuoming Li, Zhe Li, Ling Huang, Yi-You Huang, Hai-Bin Luo, Lei Guo. Discovery of 3-trifluoromethyl-substituted pyrazoles as selective phosphodiesterase 10A inhibitors for orally attenuating isoprenaline-induced cardiac hypertrophy[J]. Chinese Chemical Letters, ;2025, 36(4): 109965. doi: 10.1016/j.cclet.2024.109965 shu

Discovery of 3-trifluoromethyl-substituted pyrazoles as selective phosphodiesterase 10A inhibitors for orally attenuating isoprenaline-induced cardiac hypertrophy

Han Yuan ^{a, 1} ,
Fengcai Zhang ^{a, 1} ,
Hongzhe Huang ^{a, 1} ,
Jiafei Wu ^a ,
Yi Yang ^a ,
Wanyi Huang ^a ,
Dongjing Yang ^a ,
Zhuoming Li ^a ,
Zhe Li ^a ,
Ling Huang ^b ,
Yi-You Huang ^{b, *,} ,
Hai-Bin Luo ^{b, *,} ,
Lei Guo ^{a, *,}

a.
School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China
b.
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

hyyou@hainanu.edu.cn

hbluo@hainanu.edu.cn

guolei7@mail.sysu.edu.cn

Received Date: 3 March 2024
Revised Date: 29 April 2024
Accepted Date: 2 May 2024
Available Online: 3 May 2024

Figures(4)

Recently, MP-10, a previous drug candidate with potent inhibition of phosphodiesterase 10A (PDE10A) in clinical phase II trials for schizophrenia or Alzheimer's disease, has shown significant potential in preventing and treating cardiovascular diseases. However, its poor metabolic stability and high permeability across the blood-brain barrier (BBB) make it unsuitable for preventing and treating peripheral cardiovascular diseases. Herein, the hit-to-lead optimization was performed to discover novel 3-trifluoromethyl-substituted pyrazole derivatives as potent and selective PDE10A inhibitors. The structure-activity relationships, biological characterization, molecular mechanism, and drug-like evaluation were discussed to identify compound C7 which showed potent inhibition against PDE10A (half maximal inhibitory concentration, IC₅₀ = 11.9 nmol/L), more than 840-fold selectivity over other PDE subtypes, enhanced liver microsomes stability (T_1/₂ = 239 min) compared to MP-10 and low BBB permeability. Importantly, oral pretreatment with C7·3HCl at a dose of 5.0 mg/kg significantly attenuated the pathological and functional changes induced by isoprenaline (ISO)-induced pathological cardiac hypertrophy in mice, particularly suppressing increase of cardiac weight, atrial natriuretic peptide (ANP) and β-myosin heavy chain (β-MHC) hypertrophic markers along with cardiac fibrosis. These findings further support that targeting PDE10A provides an innovative therapeutic approach for preventing and treating cardiac diseases.
- Phosphodiesterase,
- Inhibitor,
- Drug design,
- Isoprenaline,
- Cardiac hypertrophy
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