233765-22-5Relevant academic research and scientific papers
Synthesis and analgesic activity of 2-methyl-2-[1-(3-benzoyl-4- substituted-1,4-dihydropyridyl)]acetic acid methyl esters, acetic acids, and acetamides
Agudoawu, Sammy A.,Yiu, Sai-Hay,Wallace, John L.,Knaus, Edward E.
, p. 213 - 218 (2007/10/03)
A group of 2-methyl-2-[1-(3-benzoyl-4-substituted-1,4- dihydropyridyl)]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 pK(a) 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 (1 = 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.
