Enantioselective syntheses and calcium channel modulating effects of (+)- and (−)-3-isopropyl 5-(4-methylphenethyl) 1,4-dihydro-2,6-dimethyl-4-(2-pyridyl)-3,5-pyridinedicarboxylates |
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Authors: | Nadeem Iqbal Dean Vo Carol-Anne McEwen Michael W. Wolowyk Edward E. Knaus |
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Abstract: | The (+)- and (?)-enantiomers of 3-isopropyl 5-(4-methylphenethyl) 1,4-dihydro-2,6-dimethyl-4-(2-pyridyl)-3,5-pyridinedicarboxylate were synthesized using an efficient highly enantioselective (ee ≥ 96%) variant of the Hantzsch dihydropyridine synthesis. The key step in this procedure involved the asymmetric Michael addition of a metalated chiral aminocrotonate, derived from D -valine or L -valine, respectively, to the Knoevenagel acceptor (Z)-2-isopropoxycarbonyl-1-(2-pyridyl)-but-1-en-3-one. Both enantiomers exhibited a dual cardioselective partial calcium channel agonist (positive inotropic)/smooth muscle selective calcium channel antagonist effect. The relative in vitro smooth muscle calcium channel antagonist activities of the (?):(+) enantiomers was 26:1. In contrast, the (+)-enantiomer exhibited a greater in vitro positive inotropic effect on guinea pig left atrium where the contractile force was maximally increased by 14.8% at a concentration of 1.63 × 10?8 M. © 1994 Wiley-Liss, Inc. |
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Keywords: | stereoselective synthesis chiral synthon Hantzsch esters calcium channels smooth muscle relaxation positive inotropes |
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