845302-49-0Relevant academic research and scientific papers
Design, synthesis and biological evaluation of pyrazolopyrimidinone based potent and selective PDE5 inhibitors for treatment of erectile dysfunction
Reddy, G. Lakshma,Dar, Mohd. Ishaq,Hudwekar, Abhinandan D.,Mahajan, Priya,Nargotra, Amit,Baba, Adil Manzoor,Nandi, Utpal,Wazir, Priya,Singh, Gurdarshan,Vishwakarma, Ram A.,Syed, Sajad Hussain,Sawant, Sanghapal D.
, (2019/06/11)
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.
Synthesis of 5-substituted-1H-pyrazolo[4,3-d]pyrimidin-7(6H)-one analogs and their biological evaluation as anticancer agents: mTOR inhibitors
Reddy, G. Lakshma,Guru, Santosh Kumar,Srinivas,Pathania, Anup Singh,Mahajan, Priya,Nargotra, Amit,Bhushan, Shashi,Vishwakarma, Ram A.,Sawant, Sanghapal D.
, p. 201 - 208 (2014/05/20)
A microwave assisted strategy for synthesis of series of 1H-pyrazolo[4,3-d]pyrimidin-7(6H)-ones has been developed and their biological evaluation as anticancer agents is described. The synthetic protocol involves simple procedure by oxidative coupling of 4-amino-1-methyl-3-propyl-1H-pyrazole- 5-carboxamide with different aldehydes in presence of K2S 2O8 offering 5-substituted-1H-pyrazolo[4,3-d]pyrimidin- 7(6H)-one compounds in excellent yields. The in vitro anticancer activity screening against human cancer cell lines HeLa, CAKI-I, PC-3, MiaPaca-2, A549 gave good results. The in detailed mechanistic correlation studies of compound 3m revealed that the compound shows anticancer activity through apoptosis mechanism and also inhibits mTOR with nonomolar potency. The design was based on docking with mTOR protein. The concentration dependent cell cycle analysis, western blotting experiment and nuclear cell morphology studies have been described.
