Discovery of novel pyrazolopyrimidinone analogs as potent inhibitors of phosphodiesterase type-5

Bioorg Med Chem. 2015 May 1;23(9):2121-8. doi: 10.1016/j.bmc.2015.03.005.

Sanghapal D Sawant ¹, G Lakshma Reddy ², Mohd Ishaq Dar ³, M Srinivas ², Gourav Gupta ³, Promod Kumar Sahu ⁴, Priya Mahajan ⁵, Amit Nargotra ⁵, Surjeet Singh ⁶, Subhash C Sharma ⁶, Manoj Tikoo ⁶, Gurdarshan Singh ⁴, Ram A Vishwakarma ⁷, Sajad Hussain Syed ⁸

Affiliations

1 Medicinal Chemistry Division, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu 180 001, India; AcSIR, India. Electronic address: sdsawant@iiim.ac.in.
2 Medicinal Chemistry Division, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu 180 001, India; AcSIR, India.
3 Pharmacology Division, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu 180 001, India; AcSIR, India.
4 PK-PD-Tox Division, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu 180 001, India; AcSIR, India.
5 Discovery Informatics, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu 180 001, India; AcSIR, India.
6 PK-PD-Tox Division, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu 180 001, India.
7 Medicinal Chemistry Division, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu 180 001, India; Discovery Informatics, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu 180 001, India; AcSIR, India. Electronic address: ram@iiim.res.in.
8 Pharmacology Division, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu 180 001, India. Electronic address: sshussain@iiim.ac.in.

PMID: 25801159 DOI: 10.1016/j.bmc.2015.03.005

Abstract

Cyclic guanosine monophosphate (cGMP) specific phosphodiesterase type-5 (PDE5), a clinically proven target to treat erectile dysfunction and diseases associated with lower cGMP levels in humans, is present in corpus cavernosum, heart, lung, platelets, prostate, urethra, bladder, liver, brain, and stomach. Sildenafil, vardenafil, tadalafil and avanafil are FDA approved drugs in market as PDE5 inhibitors for treating erectile dysfunction. In the present study a lead molecule 4-ethoxy-N-(6-hydroxyhexyl)-3-(1-methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-yl)benzenesulfonamide, that is, compound-4a, an analog of pyrazolopyrimidinone scaffold has been identified as selective PDE5 Inhibitor. A series of compounds was synthesized by replacing N-methylpiperazine moiety (ring-C) of sildenafil structure with different N-substitutions towards sulfonamide end. Compound-4a showed lower IC₅₀ value (1.5 nM) against PDE5 than parent sildenafil (5.6 nM) in in vitro Enzyme assay. The isoform selectivity of the compound-4a against Other PDE isoforms was similar to that of the Sildenafil. In corroboration with the in vitro data, this molecule showed better efficacy in in vivo studies using the conscious rabbit model. Also compound-4a exhibited good physicochemical properties like solubility, caco-2 permeability, cLogP along with optimal PK profile having no significant CYP Enzyme inhibitory liabilities. Discovery of these novel bioactive compounds may open a new alternative for developing novel preclinical candidates based on this drugable scaffold.

Keywords

Erectile dysfunction; PDE5 inhibitors; Pyrazolopyrimidinones; Sildenafil; cGMP.

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