Chirality in antirheumatic drugs

Kean, Walter F.; Howard-Lock, H. E.; Lock, C. J. L.

doi:10.1016/0140-6736(91)92382-c

Cited by 101 publications

(48 citation statements)

References 17 publications

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“…As noted, the molecule found in the solid state is chiral and we have previously described problems that can be caused by the use of racemic mixtures of enantiomers in the treatment of patients (11)(12)(13). This is unlikely to be a problem with azapropazone because of the rapid inversion between the two enantiomers.…”

Section: Resultsmentioning

confidence: 99%

Studies of nonsteroidal anti-inflammatory drugs: azapropazone

Fauconnier¹,

Lock²,

Bell³

et al. 1994

Can. J. Chem.

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. Can. J. Chem. 72, 382 (1994).The structure of azapropazone, 5-(dimethylamino)-9-methyl-2-propyl-1 H-pyrazolo[l,2-a][] ,2,4]benzotriazine-1,3(2H)-dione, was determined by single crystal X-ray diffraction. Crystals were orthorhombic (P212121), with a = 5.570(1) A, b = 14.593(3) A, c = 19.270(4) A, and Z = 4. Intensities were measured on a Rigaku AFC6-R diffractometer with Cu-Ka radiation and 23 16 reflections were used to determine the structure. Contrary to previous postulates, the tricyclic portion of the molecule is not planar. Azapropazone is a zwitterion with the negative charge delocalized over the P-keto-en01 system and with the proton on N(6) of the triazine ring. The nonplanarity of the molecule is caused by steric interaction of a methyl group on the exocyclic dimethylamino group with O(3) of the keto-en01 system. Bond lengths and angles are normal. NMR studies showed that at room temperature rapid inversion occurs between the two enantiomers, but this inversion slows at low temperatures with A@ = 44.9(2) kJ mol-I. The product derived from opening of the pyrazolidine ring of azapropazone by formic acid is not as previously formulated. The compound is 3-dimethylamino-7-methyl-l-valeryl-l,4-dihydro-l,2,4-benzotriazine. Its structure was determined by single crystal X-ray diffraction. Crystals were monoclinic (P21/r~), with a = 10.240(2) A, b = 12.608(3) A, c = 13.176(3) A, P = 108.46(3)", and Z = 4. Intensities were measured on a Rigaku AFC6-R diffractometer with Cu-Ka radiation and 2209 reflections were used to determine the structure. The conformation of the benzotriazine ring system was very similar to that observed in azapropazone and bond lengths and angles were normal. Cu et on a utilisC 2316 reflexions pour determiner la structure. Contrairement aux postulats antkrieurs, la portion tricyclique de la molCcule n'est pas plane. L'azapropazone est un zwitterion avec une charge negative dClocalisCe sur le systbme P-cCto-Cnolique et avec le proton sur le N(6) du noyau triazine. Le caractbre non-planaire de la molecule est provoquC par une interaction stCrique du groupe mCthyle port6 par le groupe dimCthylamino exocyclique avec le O(3) du systbme cCto-Cnolique. Les longueurs des liaisons et les angles sont normaux. Les Ctudes de RMN ont montrC que, a la temperature ambiante, il se produit une interconversion rapide entre les deux Cnantiombres, mais que l'inversion est ralentie basse tempkrature avec un A@ = 44,9(2) kJ mol-l. Le produit obtenu par ouverture du noyau pyrazolidine de l'azapropazone par l'acide formique ne correspond pas a celui qui avait kt6 formulC antkrieurement. Le composC est le 3-dimCthylamino-7-mCthyl-1-valCryl-l,4-dihydro-l,2,4-benzotriazine, On a dCterminC la structure par diffraction des rayons X par un cristal unique. Les cristaux sont monocliniques (P21/t1), avec a = 10,240(2) A, b = 12,608(3) A, c = 13,176(3) A, P = 108,46(3)" et Z = 4. On a mesurC les intensites l'aide d'un diffractombtre Rigaku AFC6-R, avec le rayonnement K a du Cu et on a utilisC 2209 rkflexions pour determi...

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Section: Resultsmentioning

confidence: 99%

Studies of nonsteroidal anti-inflammatory drugs: azapropazone

Fauconnier¹,

Lock²,

Bell³

et al. 1994

Can. J. Chem.

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“…This may result in a supraproportional bioavailability of S(+)-ibuprofen from the racemate in vivo (Romero et al, 1991) as well as a reduced risk of formation of potentially toxic metabolites from the R(-)-isomer (Kean et al, 1991), although it is not entirely clear whether this is really a stereoselective reaction (Freneaux et al, 1990). However, in our study there was no evidence for any interconversion of R(-)-ibuprofen into the S(+)-form in vitro, confirming the data of others (Knihinicki et al, 1989).…”

Section: Discussionmentioning

confidence: 99%

“…Inhibition of cyclooxygenase by these compounds resides almost exclusively in the S(+)-enantiomer (Adams et al, 1976;Kean et al, 1991). Since ibuprofen, like most of the other agents in this group, is used as a racemate, the question arises whether both stereoisomers contribute to the analgetic and antiinflammatory efficacy.…”

Section: Introductionmentioning

confidence: 99%

Equipotent inhibition by R(−)−, S(+)‐ and racemic ibuprofen of human polymorphonuclear cell function in vitro.

Villanueva

Heckenberger

Strobach

et al. 1993

Brit J Clinical Pharma

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1. The effects of racemic (rac) ibuprofen and its S(+)‐ and R(−)− enantiomers on functions of human polymorphonuclear cells (PMN) and platelets were studied in vitro. 2. Rac‐ibuprofen inhibited PMN functions (O2‐ generation, beta‐glucuronidase release, LTB4 formation). Similar IC50 values (40‐100 microM) were obtained for the S(+)‐ and R(‐ )‐enantiomers. 3. All forms of ibuprofen inhibited cyclooxygenase‐ related platelet functions (aggregation, thromboxane formation). The S(+)‐enantiomer was about twice as active as the racemate while the R(‐ )‐enantiomer was at least 10‐fold less active. This demonstrates that the S(+) is the only cyclooxygenase inhibitory component of the racemate. 4. The concentrations of rac‐ibuprofen in PMN and platelets were similar to those in the incubation medium and represented equal concentrations of the enantiomers. This indicates that neither interconversion nor tissue accumulation of the compounds occurred. 5. These data indicate that antineutrophil effects of ibuprofen on human PMN are independent of cyclooxygenase inhibition. Therefore, R(−)− ibuprofen may be superior to the S(+)‐isomer for the treatment of PMN‐ dependent inflammatory diseases. However, effective free drug concentrations may not be obtained in vivo.

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“…It has been used in the treatment of rheumatoid arthritis and hepatitis and for the prevention of infant retina disease (Phelps et al, 2001). L-penicillamine has been found to have considerable toxicity (Kean et al, 1991). Copper chelation of D-PenA has been shown to generate reactive oxygen species that are cytotoxic to human leukemia and breast cancer cells (Gupte and Mumper, 2007).…”

Section: Introductionmentioning

confidence: 99%

Direct enantiomeric TLC resolution of dl‐penicillamine using (R)‐mandelic acid and l‐tartaric acid as chiral impregnating reagents and as chiral mobile phase additive

Bhushan

Agarwal

2008

Biomedical Chromatography

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DL-Penicillamine has been resolved into its enantiomers by normal-phase TLC using L-tartaric acid as chiral impregnating reagent as well as chiral mobile phase additive, while (R)-mandelic acid has been found to be successful as a chiral impregnating reagent. The solvent system acetonitrile-methanol-water (5:1:1, v/v) was found to be successful when L-tartaric acid was used as impregnating agent while the solvent combination acetonitrile-methanol-(0.5% l-tartaric acid in water, pH 5)-glacial acetic acid (7:1:1.1:0.7, v/v) was successful as mobile phase as it contained L-tartaric acid as the chiral additive. (R)-mandelic acid was successful as chiral impregnating reagent with ethyl acetate-methanol-water (3:1:1, v/v), as the mobile phase. The effects of concentration of chiral selectors, temperature and pH were examined on enantiomeric resolution. The spots were detected with iodine vapors and the detection limits were found to be 0.12 microg for each enantiomer of penicillamine with L-tartaric acid, under both the conditions, and 0.11 microg with (R)-mandelic acid.

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Chirality in antirheumatic drugs

Cited by 101 publications

References 17 publications

Studies of nonsteroidal anti-inflammatory drugs: azapropazone

Studies of nonsteroidal anti-inflammatory drugs: azapropazone

Equipotent inhibition by R(−)−, S(+)‐ and racemic ibuprofen of human polymorphonuclear cell function in vitro.

Direct enantiomeric TLC resolution of dl‐penicillamine using (R)‐mandelic acid and l‐tartaric acid as chiral impregnating reagents and as chiral mobile phase additive

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