Abstract
Problem statement: Several studies on the synthesis of new nifedipine analogs have been carried out, but the literature reveled that no study on the synthesis and calcium channel blocking activity of the substituted ester with an amide (5-phenylcarbamoyl) moiety has been reported. Approach: Six new derivatives of m-nifedipine have been successfully synthesized by substituting an ester moiety with an amide (5-phenylcarbamoyl) moiety, using a modified Hantzsch reactions and tested for their pharmacological activities. The nifedipine analogs 1-6 were characterized and confirmed using elemental analysis, Infrared spectroscopy (IR), Nuclear Magnetic Resonance (1H NMR) and Mass spectroscopy. The purity of the compounds was ascertained by melting point and TLC. The in vitro calcium channel blocking activities were evaluated using the high K+ concentration of Porcine Coronary Artery Smooth Muscles (PCASM) assay. Results: The compounds (1-2) failed to exhibit any blocking activity (IC50 = 10−7 to 10−5 M range), while the compounds 3-6 relaxed precontracted porcine coronary artery smooth muscles with pEC50 values ranging between 4.37±0.10 (compound 3) and 6.46±0.07 (compound 5), indicating that compounds 3-6 exhibit comparable potencies in blocking calcium channels to reference drug varapamil (6.97±0.15) and m-nifedipine (6.48±0.05). Conclusion: The results of this study showed that some of the developed new compounds possess maximal calcium channel blocking effects comparable to m-nifedipine. The developed compounds in the present study will predicatively show an increased metabolic stability and consequently longer duration of actions compared to m-nifedipine and could be, therefore, suitable candidates for further optimization to be evaluated as a new class of antihypertensive drugs.
Highlights
1,4-Dihydropyridine calcium channel blockers (1,4DHPs) are an important class of drugs which induce relaxation of vascular smooth muscle, preferentially in arteries and display a negative inotropic effect on isolated cardiac muscle via binding to a high affinity binding site in 2-type voltage-dependent Ca2+ channel (Poole-Wilson et al, 2006; 1977; Richard, 2005)
The structure, molecular formulae, molecular weights, melting points and yields of the new 5-phenylcarbamoly derivatives are presented in Table 1, the results shows that the molecular weight of the prepared compounds were ranged between 424.91 - 476.30, the melting points between 108-251°C and a good yield of synthesized compounds was obtained which ranges between 53.7-75.3%
The maximal antagonistic effect, expressed as a percentage Emax value, of 106±5 observed by verapamil and of 101±1 by m-nifedipine was not achieved by all derivatives, since the highest Emax results was found by 99±1, observed for both compounds 3 and 5
Summary
1,4-Dihydropyridine calcium channel blockers (1,4DHPs) are an important class of drugs which induce relaxation of vascular smooth muscle, preferentially in arteries and display a negative inotropic effect on isolated cardiac muscle via binding to a high affinity binding site in 2-type voltage-dependent Ca2+ channel (Poole-Wilson et al, 2006; 1977; Richard, 2005). In therapy, this class of drugs has been used in general medical practice worldwide for the treatment of hypertension and vasospastic angina for over 3 decades (Richard, 2005). Anticonvulsant potency of 1,4-DHPs was dependent upon lipophilic character of the aliphatic substituents located at 3-,4- and 5-position of 1,4-DHPs skeleton (Khoshneviszadeh et al, 2009; Miri et al, 2009)
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