Synthesis and Analgesic Activity of 2-Methyl-2-[1-(3-benzoyl-4-substituted-1,4-dihydropyridyl)]acetic Acid Methyl Esters, Acetic Acids, and Acetamides

A group of 2‐methyl‐2‐[1‐(3‐benzoyl‐4‐substituted‐1,4‐dihy‐dropyridyl)] acetic acid methyl esters (7), weak acetic acids (8), and acetamides (9) were designed for evaluation as less acidic non‐ulcerogenic non‐steroidal antiinflammatory drugs (NSAIDs). In this respect, the model compound 2‐methyl‐2‐[1‐(3‐benzoyl‐4‐phenyl‐1,4‐dihydropyridyl)]acetic acid (8a), unlike traditional arylacetic acid NSAIDs, was shown to be a weak acid with a pKa of 9.17. In contrast to arylacetic acid NSAIDs, the α‐methylacetic acid sodium salt of 8a, or the methyl α‐methylacetate ester (7a) did not inhibit cyclooxygenase‐1 (COX‐1) or ‐2 (COX‐2). In vitro stability studies showed that the methyl α‐methylacetate ester (7a) acts as a prodrug to the α‐methylacetic acid derivative (8a), undergoing rapid (> 10 minutes) and quantitative conversion upon incubation with rat plasma, or incubation with rat liver homogenate (t1/2 = 25 min). In contrast, the α‐methylacetamide (9a) underwent negligible (< 2%) conversion to the α‐methylacetic acid derivative (8a) upon incubation with either rat plasma, or rat liver homogenate, for incubation times up to 24 h. The effect of a C‐3 para‐substituted‐benzoyl substituent (R1 = H, Cl, Me), a C‐4 substituent (R2 = aryl, benzyl, cyclohexyl, alkyl), and the nature of the N1‐acetic acid moiety [methyl ester (R3 = OMe), acetic acid (R3 = OH), acetamide (R3 = NH2)] on analgesic activity was determined using the 4% NaCl‐induced abdominal constriction (writhing) assay. Compounds 7—9 inhibited writhing 27—95% relative to the reference drug aspirin (58% inhibition). The analgesic potency with respect to the para‐benzoyl substituent was H > Cl or Me. Although the effect of the C‐4 R2‐substituent on analgesic activity was variable within the ester, acid and amide sub‐groups of compounds, compounds having a R2‐cyclohexyl substituent generally provided superior analgesic activity relative to those having a lipophilic alkyl substituent. The nature of the R3‐substituent (OMe, OH, NH2) was a determinant of analgesic activity where the potency order was acetic acid methyl ester > acetic acid or acetamide, except when the C‐4 R2‐substituent was cyclohexyl or benzyl where the potency order was acetamide > acetic acid methyl ester or acetic acid. Reduction of the 5,6‐olefinic bond of the 1,4‐dihydropyridyl compound (9a, 94% inhibition) to the corresponding 1,2,3,4‐tetrahydropyidyl derivative (10, 69% inhibition) reduced analgesic activity.