Title:Synthesis of Ethyl Methyl 4-aryl-1,4-dihydropyridine-3,5-dicarboxylates as
Potential Calcium Channel Blockers for Hypertension
Volume: 20
Issue: 10
Author(s): Ranju Bansal*, Priyanka Jain, Gaurav Narang, Anupreet Kaur, Carmen Calle and Rosalia Carron
Affiliation:
- University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh 160014, India
Keywords:
Dihydropyridines, calcium channel blockers, veratridine, vasodilator, antihypertensive activity, ethyl ester.
Abstract:
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.
