Generic placeholder image

Letters in Drug Design & Discovery


ISSN (Print): 1570-1808
ISSN (Online): 1875-628X

Research Article

Synthesis of Ethyl Methyl 4-aryl-1,4-dihydropyridine-3,5-dicarboxylates as Potential Calcium Channel Blockers for Hypertension

Author(s): Ranju Bansal*, Priyanka Jain, Gaurav Narang, Anupreet Kaur, Carmen Calle and Rosalia Carron

Volume 20, Issue 10, 2023

Published on: 12 September, 2022

Page: [1632 - 1644] Pages: 13

DOI: 10.2174/1570180819666220619123247

Price: $65


Aim: Several new dihydropyridine-based calcium channel blockers have been synthesized and pharmacologically evaluated for the treatment of hypertension

Background: Dihydropyridines constitute an important class of calcium channel blockers (CCBs) due to their high potency, wide heterogeneity and tremendous biological usefulness. As a follow-up to our previous studies on 4-aryl-1,4-dihydropyridines as calcium channel blockers for the treatment of hypertension, four new series of methyl ethyl ester substituted 1,4-dihydropyridines are reported.

Objectives: The aim of the work was to study the effects of unsymmetrical ester substitutions on calcium channel blocking activity of dihydropyridines (DHPs) while retaining the aminoalkoxy side chain at various positions of the 4-aryl ring. The type and location of the substituents on the 4-aryl ring have been extensively explored to study the structure-activity relationship (SAR) in this series of dihydropyridines as calcium channel blockers.

Methodology: The target DHPs were synthesized using modified Hantzsch condensation and further derivatization. The compounds were screened for their inhibitory potential against L-type calcium channels at a single concentration of 10 μM on NG108-15 cells (Neuroblastoma X Glioma). The most potent DHP 12 was also tested for its vasodilatory activity using rat thoracic aortic rings precontracted with KCl (30 mM) and in vivo antihypertensive activity in rats using the tail-cuff method.

Results: The newly synthesized DHPs displayed diversified calcium channel blocking activity with compounds 1e, 1h, 2d, 2f, 2h, 6, 9, 11, 12 and 14, producing more than 50% inhibition of veratridine response. 3-imidazolylpropoxy substituted analogue 12 turned out to be the most potent compound of the four series of compounds and produced fairly higher inhibition (78.6%) of veratridine response in comparison to nifedipine (70%) at 10 μM. In addition, compound 12 produced potent vasodilatory and antihypertensive properties.

Conclusion: Both location of the side chain and the type of substituent on methyl ethyl ester substituted 4-aryl ring affected the response of dihydropyridine derivatives towards L-type calcium channels.

Keywords: Dihydropyridines, calcium channel blockers, veratridine, vasodilator, antihypertensive activity, ethyl ester.

Graphical Abstract
Godfraind, T. Discovery and development of calcium channel blockers. Front. Pharmacol., 2017, 8, 286.
[] [PMID: 28611661]
Wang, A.L.; Iadecola, C.; Wang, G. New generations of dihydropyridines for treatment of hypertension. J. Geriatr. Cardiol., 2017, 14(1), 67-72.
[PMID: 28270844]
Bandyopadhyay, D.; Salazar, T.; Gonzalez, A. Dihydropyridines as calcium channel blockers: An Overview. J. Anal. Pharm. Res., 2017, 5(4), 3-6.
Toal, C.B.; Meredith, P.A.; Elliott, H.L. Long-acting dihydropyridine calcium-channel blockers and sympathetic nervous system activity in hypertension: A literature review comparing amlodipine and nifedipine GITS. Blood Press, 2012, 21(sup1)(Suppl. 1), 3-10.
[ 10.3109/08037051.2012.690615 ] [PMID: 22762301]
Cataldi, M.; Bruno, F. 1,4-dihydropyridines: The multiple personalities of a blockbuster drug family. Transl. Med. UniSa, 2012, 4, 12-26.
[PMID: 23905059]
Prasanna, A.D.; Pratibha, B.A. Design and synthesis of novel 4-substituted 1,4-dihydropyridine derivatives as hypotensive agents. J. Saudi Chem. Soc., 2016, 20(5), 510-516.
Steffen, H-M. Dihydropyridine calcium antagonist. J. Clin. Basic Cardiol., 1999, 2, 45-52.
El-Moselhy, T.F.; Sidhom, P.A.; Esmat, E.A.; El-Mahdy, N.A. Synthesis, docking simulation, biological evaluations and 3D-QSAR study of 1,4-dihydropyridines as calcium channel blockers. Chem. Pharm. Bull. (Tokyo), 2017, 65(10), 893-903.
[] [PMID: 28966273]
McTavish, D.; Sorkin, E.M. Verapamil. An updated review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in hypertension. Drugs, 1989, 38(1), 19-76.
[] [PMID: 2670511]
Mannhold, R. Medicinal chemistry of DHP-like calcium cntagonist. Drugs Today (Barc), 1994, 30, 103-122.
Miri, R.; Javidnia, K.; Sarkarzadeh, H.; Hemmateenejad, B. Synthesis, study of 3D structures, and pharmacological activities of lipophilic nitroimidazolyl-1,4-dihydropyridines as calcium channel antagonist. Bioorg. Med. Chem., 2006, 14(14), 4842-4849.
[] [PMID: 16603367]
Tocci, G.; Desideri, G.; Roca, E.; Calcullo, C.; Crippa, M.; De Luca, N.; Gaudio, G.V.; Lonati, L.M.; Orselli, L.; Scuteri, A.; Vulpis, V.; Acone, B.; Zaninelli, A. How to improve effectiveness and adherence to antihypertensive drug therapy: Central role of dihydropyridine calcium channel blockers in hypertension. High Blood Press. Cardiovasc. Prev., 2018, 25(1), 25-34.
[] [PMID: 29197935]
Alloui, A.; Talmant, J.M.; Duchêne-Marullaz, P. Cardiovascular profile of oxodipine, a novel dihydropyridine calcium channel blocker, in anesthetized open-chest dogs: A comparison with nitrendipine. Arch. Int. Pharmacodyn. Ther., 1991, 313, 63-75.
[PMID: 1816765]
Navadiya, K.; Tiwari, S. Pharmacology, efficacy and safety of felodipine with a focus on hypertension and angina pectoris. Curr. Drug Saf., 2015, 10(3), 194-201.
[] [PMID: 25973793]
Jain, P.; Narang, G.; Jindal, D.P.; Bansal, R.; Calle, C.; Carron, R.; Pemberton, K.; Harvey, A.L. Synthesis of a new series of 4-aryl-1,4-dihydropyridines with calcium channel blocking and vasodilatory activity. Pharmazie, 2006, 61(5), 400-405.
[] [PMID: 16724534]
Bansal, R.; Jain, P.; Calle, C.; Carron, R.; Pemberton, K.; Harvey, A.L. Synthesis of 4‐(carbonyloxyphenyl)‐1,4‐dihydropyridines as potential antihypertensive agents. Med. Chem. Res., 2012, 21, 908-921.
Liang, J-C.; Yeh, J-L.; Chiang, L-C.; Yang, Y-C.; Sheu, S-H.; Lai, W-T.; Chen, I-J. Labedipinedilol-A: A vanilloid-based α/β-adrenoceptor blocker with calcium entry blocking and long-lasting antihypertensive properties. Drug Dev. Res., 2000, 49(2), 94-108.
Rucins, M.; Plotniece, A.; Bernotiene, E.; Tsai, W-B.; Sobolev, A. Recent Approaches to Chiral 1,4-Dihydropyridines and their Fused Analogues. Catalysts, 2020, 10(9), 119.
Triggle, D.J.; Langs, D.A.; Janis, R.A. Ca2+ channel ligands: Structure-function relationships of the 1,4-dihydropyridines. Med. Res. Rev., 1989, 9(2), 123-180.
[] [PMID: 2654521]
Liang, J.C.; Yeh, J.L.; Wang, C.S.; Liou, S.F.; Tsai, C.H.; Chen, I.J. The new generation dihydropyridine type calcium blockers, bearing 4-phenyl oxypropanolamine, display α-/β-adrenoceptor antagonist and long-acting antihypertensive activities. Bioorg. Med. Chem., 2002, 10(3), 719-730.
[] [PMID: 11814861]

Rights & Permissions Print Export Cite as
© 2023 Bentham Science Publishers | Privacy Policy