Design,synthesis and evaluation of N2,N4-diaminoquinazoline based inhibitors of phosphodiesterase type 5 |
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| Authors: | Nattakarn Pobsuk Tamkeen Urooj Paracha Nattiya Chaichamnong Nattapas Salaloy Praphasri Suphakun Supa Hannongbua Kiattawee Choowongkomon Dumrongsak Pekthong Krongkarn Chootip Kornkanok Ingkaninan M. Paul Gleeson |
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| Affiliation: | 1. Department of Chemistry, Faculty of Science, Kasetsart University, Bangkok 10900, Thailand;2. Department of Pharmacy Practice, Faculty of Pharmaceutical Sciences, Naresuan University, Phitsanulok 65000, Thailand;3. Division of Applied Thai Traditional Medicine, Faculty of Public Health, Naresuan University, Phitsanulok 65000, Thailand;4. Department of Pharmaceutical Chemistry and Pharmacognosy, Faculty of Pharmaceutical Sciences, Naresuan University, Phitsanulok 65000, Thailand;5. Department of Biochemistry, Faculty of Science, Kasetsart University, Bangkok 10900, Thailand;6. Department of Physiology, Faculty of Medical Science, Naresuan University, Phitsanulok 65000, Thailand;7. Department of Biomedical Engineering, Faculty of Engineering, King Mongkut’s Institute of Technology, Ladkrabang 10520, Thailand |
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| Abstract: | We describe the design, synthesis and evaluation of a series of N2,N4-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 (IC50?=?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 EC50s of 1.63?±?0.72?µM and 2.28?±?0.74?µM respectively. |
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| Keywords: | Drug design Phosphodiesterase type 5 Quinazoline analogs Solubility |
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