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Mol Divers. 2017 Aug;21(3):533-546. doi: 10.1007/s11030-017-9738-7. Epub 2017 Apr 25.

Synthesis, pharmacological evaluation and molecular docking of pyranopyrazole-linked 1,4-dihydropyridines as potent positive inotropes.

Author information

1
Bio-organic Laboratory, Department of Chemistry, University of Delhi, Delhi, 110 007, India. rakehskp@email.com.
2
Bio-organic Laboratory, Department of Chemistry, University of Delhi, Delhi, 110 007, India.
3
Laboratory of Organic Chemistry, Department of Pharmacology and Therapeutical Chemistry, Faculty of Pharmacy, University of Barcelona, Barcelona Science Park, Baldiri Reixac 10-12, 08028, Barcelona, Spain.
4
Drug Discovery Platform, Parc Científic de Barcelona, Baldiri Reixac 10-12, 08028, Barcelona, Spain.
5
USEF Screening Platform, Centre of Research on Molecular Medicine and Chronic Diseases (CIMUS), Universidad de Santiago de Compostela (USC), Santiago de Compostela, Spain.
6
Systems Pharmacology, Research Program on Biomedical Informatics (GRIB), IMIM Hospital del Mar Medical Research Institute and University Pompeu Fabra, Doctor Aiguader 88 (PRBB), 08003, Barcelona, Catalonia, Spain.

Abstract

1,4-Dihydropyridines are well-known calcium channel blockers, but variations in the substituents attached to the ring have resulted in their role reversal making them calcium channel activators in some cases. We describe the microwave-assisted eco-friendly approach for the synthesis of pyranopyrazole-1,4-dihydropyridines, a new class of 1,4-DHPs, under solvent-free conditions in good yield, and screen them for various in silico, in vitro and in vivo activities. The in vivo experimentation results show that the compounds possess positive inotropic effect, and the docking results validate their good binding with calcium channels. Compounds 7c, 7g and 7i appear to be the most effective positive inotropes, even at low doses, and bind with the calcium channels even more strongly than Bay K 8644, a well-known calcium channel activator. The chronotropic effect for the new compounds was also studied. The target and off-target affinity profiling supported the in vivo results and revealed that the hybridized pyranopyrazole dihydropyridine scaffold has delivered new moderate hits, to be optimized, for the cytochrome P450 3A4 enzymes, opening avenues for combined pharmacological activity through standard structural modification.

KEYWORDS:

; 4-Dihydropyridines; CYP450 inhibition; Inotropic effect; Microwave synthesis; Molecular docking; Pyranopyrazole-1; Structure–activity analysis

PMID:
28444482
DOI:
10.1007/s11030-017-9738-7
[Indexed for MEDLINE]

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