title: Synthesis of new N3-substituted dihydropyrimidine derivatives as L-/T- type calcium channel blockers.
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 Cav1.2 as well against Cav3.2 are described.
authors.affiliation: 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.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Teleb
authors.affiliation: Department of Physiology & Pharmacology, Hotchkiss Brain Institute, University of Calgary, 3330 Hospital Drive NW, Calgary T2N 4N1, Canada.
authors.forename: Fang-Xiong
authors.initials: FX
authors.lastname: Zhang
authors.affiliation: Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Alexandria University, Alexandria 21521, Egypt.
authors.forename: Ahmed M
authors.initials: AM
authors.lastname: Farghaly
authors.affiliation: Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Alexandria University, Alexandria 21521, Egypt.
authors.forename: Omaima M
authors.initials: OM
authors.lastname: Aboul Wafa
authors.affiliation: Department of Chemistry, College of Science, Louisiana State University, Baton Rouge, LA 70803, USA.
authors.forename: Frank R
authors.initials: FR
authors.lastname: Fronczek
authors.affiliation: Department of Physiology & Pharmacology, Hotchkiss Brain Institute, University of Calgary, 3330 Hospital Drive NW, Calgary T2N 4N1, Canada.
authors.forename: Gerald W
authors.initials: GW
authors.lastname: Zamponi
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, South Dakota State University, Brookings, SD 57007, USA. Electronic address: Hesham.Fahmy@sdstate.edu.
authors.forename: Hesham
authors.initials: H
authors.lastname: Fahmy
mesh_terms: D002121:Calcium Channel Blockers / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D020746:Calcium Channels, L-Type / Q000378:metabolism*; D018360:Crystallography, X-Ray; D004095:Dihydropyridines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D057809:HEK293 Cells; D006801:Humans; D006973:Hypertension / Q000188:drug therapy; D008958:Models, Molecular
chemical_list: D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D004095:Dihydropyridines
keywords: Ca(v)1.2; Ca(v)3.2; Dihydropyridines; Dihydropyrimidines; L-type calcium channel blockers; T-type calcium channel blockers; Whole patch clamp technique