SYNTHESIS AND SMOOTH-MUSCLE CALCIUM-CHANNEL ANTAGONIST EFFECTS OF ALKYL 4,4-DIMETHYLOXAZOLIN-2-YL)]-3-PYRIDINECARBOXYLATES

A group of racemic alkyl 1,4-dihydro-2,6-dimethyl-4-(3- or 4,4-dimethy loxazolin-2-yl)]-3-pyridinecarboxylates 11a-e were prepared by using t he Hantzsch reaction involving condensation of the Knoevenagel adducts 9a-e with -dihydro-4,4-dimethyloxazolin-2-yl]-propen-2-amine (10). In contrast, the 4-(2-pyridinyl) analogue 11f was prepared by thionyl ch loride mediated cyclization of the 5-{N-(1,1-dimethyl-2-hydroxyethyl)a minocarbonyl} moiety of 16 to the 5-[2-(4,5-dihydro-4,4-dimethyloxazol in-2-yl)] ring system (11f), In vitro calcium channel antagonist activ ity was determined by using the guinea pig ileum longitudinal smooth m uscle (GPILSM) assay. Compared to the reference drug nifedipine (IC50 = 1.43 x 10(-8) M), the title compounds 11 exhibited weak calcium chan nel antagonist activity (10(-5) to 10(-6) M range). A comparison of co mpounds 11 having a C-4 3-pyridinyl substituent showed that with respe ct to the alkyl ester R(2)-subsituent, the relative potency order was i-Bu (11c) greater than or equal to i-Pr (11e) > Me (11a). The point o f attachment of the C-4 pyridinyl substituent in the isopropyl ester i someric series of compounds was a determinant of activity where the po tency profile was 4-py (11d) greater than or equal to 3-py (11e) > 2-p y (11f). Although less effective, the 4,5-dihydro-4,4-dimethyloxazolin -2-yl moiety acts as a bioisostere of the alkyl ester substituent pres ent in classical 1,4-dihydropyridine calcium channel antagonists, The 4,5-dihydro-4,4-dimethyl-oxaxolin-2-yl ring system is not an effective bioisostere of the 3-nitro group present in 1,4-dihydropyridine calci um channel agonists since isopropyl -4,4-dimethyloxazolin-2-yl)]-3-pyr idinecarboxylate (11f) produced a modest-10% increase in the in vitro contractile force of guinea pig left atrium at a concentration of 1.64 x 10(-7) M, relative to the reference 3-nitro analogue 1 (EC(50) = 9. 6 x 10(-6) M).