Synthesis of 2-methyl-2-[1-(3-benzoyl-4-phenyl-1,4-dihydropyridyl)]acetic acid methyl ester, acetic acid, and acetamide analogs as potential antiarthritic agents

Agudoawu, Sammy A.; Yiu, Sai-hay; Knaus, Edward E.

doi:10.1139/v97-131

Cited by 2 publications

(7 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The 1 H NMR spectra of the methyl acetate derivatives (7a-o) exhibit dual resonances (approximate ratio of about 1:1) for some of the dihydropyridyl ring and ester OMe protons, as reported previously [1] .…”

Section: Chemistrysupporting

confidence: 80%

“…[b] The synthesis and characterization was reported previously [1] . [ The compound was characterized as the methyl ester (7) prepared by adding a solution of diazomethane in MeOH to a solution of the acid (8).…”

Section: Resultsmentioning

confidence: 99%

“…Methyl 2-methyl-2-[1-(3-benzoyl-4-phenyl-1,4-dihydropyridyl)]ac etate (7a) and 2-methyl-2-[1-(3-benzoyl-4-cyclohexyl-1,4-dihydropyridyl)]acetamide (9c) exhibited the most potent analgesic activity (95% inhibition) relative to the reference drug aspirin (58% inhibition) for a 50 mg/kg intraperitoneal dose. 1 H NMR spectra were recorded on a Bruker AM-300 spectrometer. Chemical shifts are reported in ppm (δ) values relative to TMS as internal reference.…”

Section: Resultsmentioning

confidence: 99%

“…In an earlier study, we described the synthesis and characterization of 2-methyl-2-[1-(3-benzoyl-4-phenyl-1,4-dihydropyridyl)]acetic acid methyl ester (1a), acetic acid sodium salt (1b), and acetamide (1c) diastereomers (4R*,2R*; 4S*,2S*; 4R*,2S*; 4S*,2R*) [1] . Aryl-and heteroarylacetic acid derivatives that exhibit analgesic and non-steroidal antiinflammatory (NSAID) activities possess several common structural features.…”

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

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

Yiu

Wallace

et al. 1999

Arch. Pharm. Pharm. Med. Chem.

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Section: Chemistrysupporting

confidence: 80%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

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

Yiu

Wallace

et al. 1999

Arch. Pharm. Pharm. Med. Chem.

Self Cite

View full text Add to dashboard Cite

show abstract

“…Previously, we described the synthesis and characterization of methyl 2-methyl-2-[1-(3-benzoyl-4-phenyl-1,4-dihydropyridyl)]acetate diastereomers (9) which could be separated into a solid product (9a-solid, 4R*,2R* and 4S*,2S*) and an oil product (9b-oil, 4R*,2S* and 4S*,2R*), each consisting of a mixture of two diastereomers that differ in configuration (R* or S*) at the 1,4dihydropyridine C-4 position and the -CH(Me)CO 2 Me moiety [Agudoawu et al, 1997]. As part of our program to design selective COX-2 inhibitors, we now describe the elaboration of diastereomers 9-solid to the hitherto unknown methyl 2-methyl-2- [2-(4-benzoyl-5-phenyl-7halo-2-azabicyclo[4.1.0]hept-3-ene)]acetates (10-15), and acetamide derivative (16), for evaluation as analgesicantiinflammatory agents.…”

Section: Introductionmentioning

confidence: 99%

Design and syntheses of methyl 2‐methyl‐2‐[2‐(4‐benzoyl‐5‐phenyl‐7‐halo‐2‐azabicyclo[4.1.0]hept‐3‐ene)]acetates: novel inhibitors of cyclooxygenase‐2 (COX‐2) with analgesic‐antiinflammatory activity

Agudoawu

Habeeb

et al. 2000

Drug Development Research

Self Cite

View full text Add to dashboard Cite

A group of methyl 2‐methyl‐2‐[2‐(4‐benzoyl‐5‐phenyl‐7‐halo‐2‐azabicyclo[4.1.0]hept‐3‐ene)]acetates (10–15), and the related acetamide derivative (16), that possess a variety of C‐7 substituents (Br, Cl, F, H), were designed for evaluation as analgesic‐antiinflammatory agents. The effect of the C‐7 substituent(s) and the nature of the acetic acid ester (R1 = Ome) or acetamide (R1 = NH2) moiety on analgesic activity was determined using a 4% NaCl‐induced abdominal constriction assay. Compounds 10–16 inhibited writhing by 36–82%, relative to the reference drugs aspirin (58% inhibition) and celecoxib (62% inhibition). The nature of the C‐7 substituents was a determinant of analgesic activity in the 7,7‐dihalo group of compounds where the relative activity profile was 7‐Cl2 > 7‐Br2 > 7‐F2 > 7‐Cl,7‐F, and for 7‐monohalo compounds where the potency order was 7‐Br > 7‐Cl. Elaboration of the 7,7‐dibromo methyl acetate ester (10) to the corresponding acetamide derivative (16) enhanced analgesic activity. The nature of the 7‐halo substituent(s) in the 7,7‐dihalo group of compounds was a determinant of antiinflammatory activity, determined using the carrageenan‐induced rat paw edema assay, where the relative potency order was 7‐Br2 > 7‐Cl2 > 7‐F2 > 7‐Cl,7‐F. The most potent 7,7‐dibromo compound (10) inhibited inflammation by 62%, relative to the reference drug ibuprofen (44%), and 10 inhibited COX‐2 (IC50 = 26.4 μM) and COX‐1 (IC50 = 227 μM) for a COX‐2 selectivity index of 8.6. Docking 10 in the active site of human COX‐2 showed it binds in the center of the COX‐2 binding site with the C‐5 phenyl ring oriented toward the acetylation site (Ser530), and the phenyl group of the C‐4 benzoyl moiety oriented in the vicinity of the COX‐2 secondary binding pocket near Val523. Drug Dev. Res. 49:75–84, 2000. © 2000 Wiley‐Liss, Inc.

show abstract

Synthesis of 2-methyl-2-[1-(3-benzoyl-4-phenyl-1,4-dihydropyridyl)]acetic acid methyl ester, acetic acid, and acetamide analogs as potential antiarthritic agents

Cited by 2 publications

References 0 publications

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

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

Design and syntheses of methyl 2‐methyl‐2‐[2‐(4‐benzoyl‐5‐phenyl‐7‐halo‐2‐azabicyclo[4.1.0]hept‐3‐ene)]acetates: novel inhibitors of cyclooxygenase‐2 (COX‐2) with analgesic‐antiinflammatory activity

Contact Info

Product

Resources

About