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Design, synthesis and evaluation of N 2 ,N 4 -diaminoquinazoline based inhibitors of phosphodiesterase type 5
Author(s)
Pobsuk, Nattakarn
Paracha, Tamkeen Urooj
Chaichamnong, Nattiya
Salaloy, Nattapas
Suphakun, Praphasri
Hannongbua, Supa
Choowongkomon, Kiattawee
Pekthong, Dumrongsak
Chootip, Krongkarn
Ingkaninan, Kornkanok
Gleeson, M. Paul
Date Issued
January 15, 2019
Type
Article
Abstract
We describe the design, synthesis and evaluation of a series of N 2 ,N 4 -diaminoquinazoline analogs as PDE5 inhibitors. Twenty compounds were prepared and these were assessed in terms of their PDE5 and PDE6 activity, ex-vivo vasodilation response, mammalian cytotoxicity and aqueous solubility. Molecular docking was used to determine the binding mode of the series and this was demonstrated to be consistent with the observed SAR. Compound 15 was the most active PDE5 inhibitor (IC 50 = 0.072 ± 0.008 µM) and exhibited 4.6-fold selectivity over PDE6. Ex-vivo assessment of 15 and 22 in a rat pulmonary artery vasodilation model demonstrated EC 50 s of 1.63 ± 0.72 µM and 2.28 ± 0.74 µM respectively.
Citation
Bioorganic and Medicinal Chemistry Letters, 29(2), 267-270, 2019