title: Discovery of novel pyrazolopyrimidinone analogs as potent inhibitors of phosphodiesterase type-5.
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.
authors: Medicinal Chemistry Division, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu 180 001, India; AcSIR, India. Electronic address: sdsawant@iiim.ac.in.
authors: Sanghapal D
authors: SD
authors: Sawant
authors: Medicinal Chemistry Division, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu 180 001, India; AcSIR, India.
authors: G
authors: G
authors: Lakshma Reddy
authors: Pharmacology Division, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu 180 001, India; AcSIR, India.
authors: Mohd Ishaq
authors: MI
authors: Dar
authors: Medicinal Chemistry Division, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu 180 001, India; AcSIR, India.
authors: M
authors: M
authors: Srinivas
authors: Pharmacology Division, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu 180 001, India; AcSIR, India.
authors: Gourav
authors: G
authors: Gupta
authors: PK-PD-Tox Division, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu 180 001, India; AcSIR, India.
authors: Promod Kumar
authors: PK
authors: Sahu
authors: Discovery Informatics, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu 180 001, India; AcSIR, India.
authors: Priya
authors: P
authors: Mahajan
authors: Discovery Informatics, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu 180 001, India; AcSIR, India.
authors: Amit
authors: A
authors: Nargotra
authors: PK-PD-Tox Division, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu 180 001, India.
authors: Surjeet
authors: S
authors: Singh
authors: PK-PD-Tox Division, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu 180 001, India.
authors: Subhash C
authors: SC
authors: Sharma
authors: PK-PD-Tox Division, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu 180 001, India.
authors: Manoj
authors: M
authors: Tikoo
authors: PK-PD-Tox Division, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu 180 001, India; AcSIR, India.
authors: Gurdarshan
authors: G
authors: Singh
authors: 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.
authors: Ram A
authors: RA
authors: Vishwakarma
authors: Pharmacology Division, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu 180 001, India. Electronic address: sshussain@iiim.ac.in.
authors: Sajad Hussain
authors: SH
authors: Syed
mesh_terms: D000818:Animals; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5 / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D015394:Molecular Structure; D058986:Phosphodiesterase 5 Inhibitors / Q000008:administration & dosage / Q000737:chemistry* / Q000494:pharmacology*; D011720:Pyrazoles / Q000737:chemistry* / Q000494:pharmacology*; D011744:Pyrimidinones / Q000737:chemistry* / Q000494:pharmacology*; D011817:Rabbits; D013329:Structure-Activity Relationship
chemical_list: D058986:Phosphodiesterase 5 Inhibitors; D011720:Pyrazoles; D011744:Pyrimidinones; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5
keywords: Erectile dysfunction; PDE5 inhibitors; Pyrazolopyrimidinones; Sildenafil; cGMP