A group of 3‐(hydroxyalkyl) 5‐alkyl 1,4‐dihydro‐2,6‐dimethyl‐4‐aryl‐3,5‐pyridinedicarboxylates (11–15) were prepared using a modified Hantzsch reaction, which were then elaborated to valproate (16–18), 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 (IC50 = 10–7 to 10–10 M range), relative to the reference drug nimodipine (IC50 = 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 1‐methyl‐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 [CO2(CH2)nO2CCH(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 [CO2(CH2)2O2C‐n‐Bu] also provided protection in the MES screen, whereas those having a 1‐methyl‐1,4‐dihydropyridyl‐3‐carbonyloxy CDS moiety were inactive. Drug Dev. Res. 48:26–37, 1999. © 1999 Wiley‐Liss, Inc.