Portal de Periódicos da CAPES

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

1999; Wiley; Volume: 48; Issue: 1 Linguagem: Inglês

10.1002/(sici)1098-2299(199909)48

1098-2299

Sai‐hay Yiu, Edward E. Knaus,

Coordination Chemistry and Organometallics

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.