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Pyrazolopyrimidinone Based Selective Inhibitors of PDE5 for the Treatment of Erectile Dysfunction |
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| Authors: | Abhinandan D Hudwekar Pankul Kotwal Mohd Ishaq Dar Shilpi Balgotra Ashish Dogra Jaspreet Kour Santosh S Chobe Utpal Nandi Sajad Hussain Syed Sanghapal D Sawant |
| Institution: | 1. Natural Products and Medicinal Chemistry Division, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu, 180001 UT of J&K, India
Academy of Scientific and Innovative Research, Ghaziabad, 201002 Uttar Pradesh, India Department of Biochemistry, Vanderbilt University, School of Medicine, Nashville, Tennessee, 37232-0146 United States;2. PK-PD Tox Division, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu, 180001 UT of J&K, India Academy of Scientific and Innovative Research, Ghaziabad, 201002 Uttar Pradesh, India;3. Pharmacology Division, CSIR-Indian Institute of Integrative Medicine, Sanat Nagar, Srinagar- 190005 UT of J&K, India Academy of Scientific and Innovative Research, Ghaziabad, 201002 Uttar Pradesh, India;4. Natural Products and Medicinal Chemistry Division, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu, 180001 UT of J&K, India;5. Natural Products and Medicinal Chemistry Division, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu, 180001 UT of J&K, India Academy of Scientific and Innovative Research, Ghaziabad, 201002 Uttar Pradesh, India;6. Department of Chemistry, Loknete Vyankatrao Hiray Arts, Science and Commerce College, Nashik, 422003 Maharashtra, India;7. Pharmacology Division, CSIR-Indian Institute of Integrative Medicine, Sanat Nagar, Srinagar- 190005 UT of J&K, India |
| Abstract: | Continuing research with our earlier finding of sildenafil based analogs in the search of new inhibitors of PDE5 for erectile dysfunction suggested that there is a scope of modifications at N-methylpiperazine ring with hydrophobic region followed by hydrogen bond donor or acceptor region. However, the leads identified earlier had some limitations like poor pharmacokinetic (PK) profile, low aqueous solubility and poor bioavailability. In this direction, a new series of sildenafil based analogs were designed, synthesized and screened for their PDE5 inhibitory activity. In this series compound 18 was found to have excellent in vitro activity with selectivity towards PDE5 isozyme, also the in vivo activity and pharmacokinetic profile was excellent. The cyp inhibition and CaCO2 permeability was also excellent for compound 18 . |
| Keywords: | erectile dysfunction PDE5 inhibitors PDE6 enzyme pyrazolopyrimidinone scaffold sildenafil |