Discovery of Potent, Selective, and Orally Bioavailable Inhibitors against Phosphodiesterase-9, a Novel Target for the Treatment of Vascular Dementia

  • J Med Chem. 2019 Apr 25;62(8):4218-4224. doi: 10.1021/acs.jmedchem.8b01041.
Yinuo Wu  1 ,  Qian Zhou  1 ,  Tianhua Zhang  1 ,  Zhe Li  1 ,  Yi-Ping Chen  1 ,  Pei Zhang  1 ,  Yan-Fa Yu  1 ,  Haiju Geng  1 ,  Yi-Jing Tian  1 ,  Chen Zhang  1 ,  Yu Wang  2 ,  Jian-Wen Chen  1 ,  Yan Chen  3 ,  Hai-Bin Luo  1
Affiliations
  • 1. School of Pharmaceutical Sciences , Sun Yat-sen University , Guangzhou 510006 , P. R. China.
  • 2. Infinitus (China) Co. Ltd. , Guangzhou 510663 , P. R. China.
  • 3. College of Pharmaceutical Sciences , Zhejiang University of Technology , Hangzhou 310014 , P. R. China.
PMID: 30916555 DOI: 10.1021/acs.jmedchem.8b01041
Abstract

To identify phosphodiesterase-9 (PDE9) as a novel target for the treatment of vascular dementia (VaD), a series of pyrazolopyrimidinone analogues were discovered based on a hit 1. Hit-to-lead optimization resulted in a potent inhibitor 2 with excellent selectivity and physicochemical properties to enable in vivo studies. Oral administration of 2 (5.0 mg/kg) caused notable therapeutic effects in the VaD mouse model, providing a promising lead or chemical probe for investigating the biological functions of PDE9 inhibition.

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