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.
journal_name
Eur J Med Chemjournal_title
European journal of medicinal chemistryauthors
Teleb M,Zhang FX,Farghaly AM,Aboul Wafa OM,Fronczek FR,Zamponi GW,Fahmy Hdoi
10.1016/j.ejmech.2017.03.080subject
Has Abstractpub_date
2017-07-07 00:00:00pages
52-61eissn
0223-5234issn
1768-3254pii
S0223-5234(17)30249-0journal_volume
134pub_type
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