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

Abstract

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.

Design of 1,4-Dihydropyridine Hybrid Benzamide Derivatives: Synthesis and Evaluation of Analgesic Activity and Their Molecular Docking Studies

“…These modulations at the C3-and C5-positions alter tissue selectivity. [11][12][13] The new therapeutic utility of 1,4-dihydropyridine derivatives is a breakthrough in current clinical trials, encompassing their antimicrobial, 14,15 anticoagulant, 16 antihypertensive, 17 analgesic, 18,19 anticancer, 20 cytotoxic, 21 antitumor activities. 22,23 For instance, we previously reported the anticoagulant and antimicrobial activities of 1,4-dihydropyridine derivatives 24 and other pharmaceutical activities such as analgesic 25,26 and anti-inflammatory.…”

Antimicrobial, anticoagulant, and cytotoxic evaluation of multidrug resistance of new 1,4-dihydropyridine derivatives

“…The development of multidrug resistance is a major obstacle in pharmacology, requiring the constant development of new therapeutics. 1,4-Dihydropyridine derivatives display a broad spectrum of pharmacological activities such as antitumor (Boer and Gekeler, 1995), antihypertensive (Wenzel et al, 2000), anticonvulsant (Surendra Kumar et al, 2010), cytotoxic (Miri et al, 2011), and significant of analgesic activities (Agudoawu et al, 1999, Warren and Knaus, 1981, Ulloora et al, 2013). Fig.…”

Optimization of gas chromatographic method for the enantioseparation of arylpropionic non-steroidal anti-inflammatory drug methyl esters

“…Moreover, some recent studies have shown that application of profen prodrugs could additionally reduce the risk of gastrointestinal injury. Among other profen prodrug types esters of arylpropionic acids have been introduced [8][9][10][11][12][13] The active enantiomers of profens can be synthesized with excellent enantiomeric excesses by stereoselective esterification of racemic carboxylic acid using the enzyme, which react only with one enantiomer to give corresponding carboxylic acid esters. Yield of corresponding esters was analyzed by gas chromatography (GC) [14][15][16][17].…”