Synthesis of valproate, valerate, and 1-methyl-1, 4-dihydropyridyl-3-carbonyloxy ester derivatives of Hantzsch 1,4-dihydropyridines as potential prodrugs and their evaluation as calcium channel antagonist and anticonvulsant agents
✍ Scribed by Sai-hay Yiu; Edward E. Knaus
- Publisher
- John Wiley and Sons
- Year
- 1999
- Tongue
- English
- Weight
- 340 KB
- Volume
- 48
- Category
- Article
- ISSN
- 0272-4391
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✦ Synopsis
A group of 3-(hydroxyalkyl) 5-alkyl 1,4-dihydro-2,6-dimethyl-4-aryl-3,5-pyridinedicarboxylates (1115) were prepared using a modified Hantzsch reaction, which were then elaborated to valproate (1618), valerate (19, 20), and 1-methyl-1,4-dihydropyridyl-3-carbonyloxy (25, 26) derivatives. Alternatively, the valproate derivative 3-(2-n-propylpentanoyloxymethyl) 5-isopropyl 1,4-dihydro-2,6-dimethyl-4-(2,3-dichlorophenyl)-3,5-pyridinedicarboxylate (34) was prepared by the reaction of isopropyl 1,4-dihydro-2,6-dimethyl-4-(2,3-dichlorophenyl)-3,5-pyridinedicarboxylate (30) with chloromethyl valproate (33). This class of lipophilic compounds possess partition coefficients (Kp) in the 149-452 range, relative to the reference drug nimodipine (Kp = 187). All compounds exhibited potent calcium channel antagonist (CCA) activity (IC 50 = 10 -7 to 10 -10 M range), relative to the reference drug nimodipine (IC 50 = 1.49 × 10 -8 M). CCA structure-activity relationships showed the parent C-3 2-hydroxyethyl compounds were more potent than their valproate derivatives, but less active than their valerate derivatives. Compounds having a 1methyl-1,4-dihydropyridyl-3-carbonyloxy chemical delivery system (CDS) were approximately equiactive to the parent C-3 2-hydroxyethyl compounds. Anticonvulsant activity was determined in the maximal electroshock (MES) and subcutaneous metrazol (scMet) screens. 3-(2-Hydroxyethyl) 5-isopropyl 1,4-dihydro-2,6-dimethyl-4-(2,3-dichlorophenyl)-3,5-pyridinedicarboxylate (12) provided modest protection in the MES and scMet screens. In the C-3 valproate [CO 2 (CH 2 )nO 2 CCH(n-Pr) 2 ] group of compounds, those possessing an ethylene spacer (n = 2) provided protection in the MES screen, whereas those having a propylene spacer (n = 3) or methylene spacer (n = 1) were inactive. Related C-3 valerate esters [CO 2 (CH 2 ) 2 O 2 C-n-Bu] also provided protection in the MES screen, whereas those having a 1-methyl-1,4-dihydropyridyl-3carbonyloxy CDS moiety were inactive.