"Synthesis of new N3-substituted dihydropyrimidine derivatives as L-/T-" by Mohamed Teleb, Fang-Xiong Zhang et al.

Faculty Publications

Title

Synthesis of new N3-substituted dihydropyrimidine derivatives as L-/T- type calcium channel blockers

Authors

Mohamed Teleb, Department of Pharmaceutical Sciences, College of Pharmacy, South Dakota State University, Brookings, SD 57007, USA; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Alexandria University, Alexandria 21521, Egypt.
Fang-Xiong Zhang, Department of Physiology & Pharmacology, Hotchkiss Brain Institute, University of Calgary, 3330 Hospital Drive NW, Calgary T2N 4N1, Canada.
Ahmed M. Farghaly, Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Alexandria University, Alexandria 21521, Egypt.
Omaima M. Aboul Wafa, Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Alexandria University, Alexandria 21521, Egypt.
Frank R. Fronczek, Department of Chemistry, College of Science, Louisiana State University, Baton Rouge, LA 70803, USA.
Gerald W. Zamponi, Department of Physiology & Pharmacology, Hotchkiss Brain Institute, University of Calgary, 3330 Hospital Drive NW, Calgary T2N 4N1, Canada.
Hesham Fahmy, Department of Pharmaceutical Sciences, College of Pharmacy, South Dakota State University, Brookings, SD 57007, USA. Electronic address: Hesham.Fahmy@sdstate.edu.

Document Type

Article

Publication Date

7-7-2017

Abstract

Cardiovascular diseases (CVDs) are the main cause of deaths worldwide. Up-to-date, hypertension is the most significant contributing factor to CVDs. Recent clinical studies recommend calcium channel blockers (CCBs) as effective treatment alone or in combination with other medications. Being the most clinically useful CCBs, 1,4-dihydropyridines (DHPs) attracted great interest in improving potency and selectivity. However, the short plasma half-life which may be attributed to the metabolic oxidation to the pyridine-counterparts is considered as a major limitation for this class. Among the most efficient modifications of the DHP scaffold, is the introduction of biologically active N3-substituted dihydropyrimidine mimics (DHPMs). Again, some potent DHPMs showed only in vitro activity due to first pass effect through hydrolysis and removal of the N3-substitutions. Herein, the synthesis of new N3-substituted DHPMs with various functionalities linked to the DHPM core via two-carbon spacer to guard against possible metabolic inactivation is described. It was designed to keep close structural similarities to clinically efficient DHPs and the reported lead DHPMs analogues, while attempting to improve the pharmacokinetic properties through better metabolic stability. Applying whole batch clamp technique, five compounds showed promising L- and T- type calcium channel blocking activity and were identified as lead compounds. Structure requirements for selectivity against Ca1.2 as well against Ca3.2 are described.

Publication Source (Journal or Book title)

European journal of medicinal chemistry

First Page

Last Page

Recommended Citation

Teleb, M., Zhang, F., Farghaly, A. M., Aboul Wafa, O. M., Fronczek, F. R., Zamponi, G. W., & Fahmy, H. (2017). Synthesis of new N3-substituted dihydropyrimidine derivatives as L-/T- type calcium channel blockers. European journal of medicinal chemistry, 134, 52-61. https://doi.org/10.1016/j.ejmech.2017.03.080

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