Design and synthesis of pyrazolo[3,4-d]pyrimidinone derivatives: Discovery of selective phosphodiesterase-5 inhibitors

Mohamed A Shaaban; Yaseen A M M Elshaier; Ali H Hammad; Nahla A Farag; Haredy Hassan Haredy; Ahmed A AbdEl-Ghany; Khaled O Mohamed

doi:10.1016/j.bmcl.2020.127337

Design and synthesis of pyrazolo[3,4-d]pyrimidinone derivatives: Discovery of selective phosphodiesterase-5 inhibitors

Bioorg Med Chem Lett. 2020 Aug 15;30(16):127337. doi: 10.1016/j.bmcl.2020.127337. Epub 2020 Jun 12.

Authors

Mohamed A Shaaban¹, Yaseen A M M Elshaier², Ali H Hammad³, Nahla A Farag⁴, Haredy Hassan Haredy⁵, Ahmed A AbdEl-Ghany⁶, Khaled O Mohamed⁷

Affiliations

¹ Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Cairo University, 11562, Egypt.
² Organic & Medicinal Chemistry Department, Faculty of Pharmacy, University of Sadat City, Sadat City, Menoufia, 32958, Egypt. Electronic address: yaseenelshaier@azher.edu.eg.
³ Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy (Boys), Al-Azahar University, Cairo 11884, Egypt.
⁴ Pharmaceutical Chemistry Department, Faculty of Pharmacy, Misr International University, Cairo 11431, Egypt.
⁵ Department of Pharmacology, Faculty of Medicine, Al-Azher University, 71524 Assiut, Egypt.
⁶ Biochemistry Department, Faculty of Pharmacy, Al-Azher University, 71524 Assiut, Egypt; Biochemistry Department, Faculty of Pharmacy, Nahda University, Benisuif, Egypt.
⁷ Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Cairo University, 11562, Egypt. Electronic address: khaled.mohamed@pharma.cu.edu.eg.

PMID: 32631538
DOI: 10.1016/j.bmcl.2020.127337

Abstract

A novel series of 1,6-disubstituted pyrazolo[3,4-d]pyrimidin-7-one derivatives, 2a-h, 4a-d, 5 and 6, were successfully synthesized, which showed promising, and potent inhibition of phosphodiesterase 5 (PDE5). The inhibitory activities of 5, 4b, 2a, 2d, 2f, 4d and 4a against PDE5 were similar to that of sildenafil (100%). These compounds exhibited potent relaxant effects on isolated rat cavernosum tissue with pEC₅₀ values ranging from 8.31 to 5.16 µM. Pyrazolo[3,4-d]pyrimidin-7-one scaffolds have been rationally designed via consecutive molecular modelling studies prior to their synthesis and biological evaluation. In addition, the results of the pharmacophore-based virtual screening revealed that 1v0p_PVB might have promising activity as a PDE-5 inhibitor.

Keywords: Cavernosum tissue; Molecular modelling; PDE-5 inhibitors; Phosphodiesterase 5 (PDE5); Pyrazolo[3,4-d]pyrimidin-7-one; Sildenafil.

MeSH terms

Animals
Cyclic Nucleotide Phosphodiesterases, Type 5 / metabolism*
Dose-Response Relationship, Drug
Drug Discovery*
Humans
Male
Molecular Structure
Phosphodiesterase 5 Inhibitors / chemical synthesis
Phosphodiesterase 5 Inhibitors / chemistry
Phosphodiesterase 5 Inhibitors / pharmacology*
Pyrazoles / chemical synthesis
Pyrazoles / chemistry
Pyrazoles / pharmacology*
Pyrimidines / chemical synthesis
Pyrimidines / chemistry
Pyrimidines / pharmacology*
Rats
Structure-Activity Relationship

Substances

Phosphodiesterase 5 Inhibitors
Pyrazoles
Pyrimidines
pyrazolo(3,4-d)pyrimidine
Cyclic Nucleotide Phosphodiesterases, Type 5