Design,synthesis and biological evaluation of pyrazolopyrimidinone based potent and selective PDE5 inhibitors for treatment of erectile dysfunction |
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| Institution: | 1. Pharmacology Division, CSIR-Indian Institute of Integrative Medicine, Jammu 180001, India;2. Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India;3. Quality Management and Instrumentation Division, CSIR-Indian Institute of Integrative Medicine, Jammu 180001, India;1. Pharmaceutical Organic Chemistry Department, Cairo University, Kasr El-Eini street 11562, Cairo, Egypt;2. Pharmaceutical Chemistry Department, Alexandria University, Alexandria 21521, Egypt;3. Pharmaceutical Chemistry Department, Nahda University, Beni-Suef 62513, Egypt;4. Pharmacology and Toxicology Department, University of Sadat City, Menufya, Egypt;5. Department of Pharmaceutics, Alexandria University, Alexandria 21521, Egypt;6. Biochemistry Department, Al-Azhar University, Assuit Branch, Egypt;7. Biochemistry Department, Nahda University, Beni-Suef 62513, Egypt;8. Organic and Medicinal Chemistry Department, University of Sadat City, Menufya, Egypt |
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| Abstract: | Our previous discovery of series of pyrazolopyrimidinone based PDE5 inhibitors led to find potent leads but with low aqueous solubility and poor bioavailability, and low selectivity. Now, a new series of same pyrazolopyrimidinone scaffold is designed, synthesized and evaluated for its PDE5 inhibitory potential. In this study, some of the molecules are found more potent and selective PDE5 inhibitors in vitro than sildenafil. The studies revealed that compound 5 is 20 fold selective to PDE5 against PDE6. As PDE6 enzyme is involved in the phototransduction pathway in the retina and creates distortion problem, the selectivity for PDE5 specifically against PDE6 enzyme is preferred for any development candidate and in present study, compound 5 has been found to be devoid of this liability of selectivity issue. Moreover, compound 5 has shown excellent in vivo efficacy in conscious rabbit model, it's almost comparable to sildenafil. The preclinical pharmacology including pharmacokinetic and physicochemical parameter studies were also performed for compound 5, it was found to have good PK properties and other physicochemical parameters. The development of these selective PDE5 inhibitors can further lead to draw strategies for the novel preclinical and/or clinical candidates based on pyrazolopyrimidinone scaffold. |
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| Keywords: | Pyrazolopyrimidinone derivatives PDE5 inhibitors PDE6 enzyme Sildenafil Erectile dysfunction |
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