Captopril, oxidation

Lee TY, Notari RE. Kinetics and mechanism of captopril oxidation in aqueous solution under controlled oxygen partial pressure. Pharm Res 1987 4 98-103. 

Methods for determination of thiol drugs (i.e., captopril [21-25], penicillamine [26-28], hydrochlorothiazide [24, 25, 29, 30], and tiopronin [31, 32]) have been developed. These methods are based on CL from a cerium (IV) oxidation system sensitized by adequate fluorophores such as quinine and rhodamine B. By using HPLC-coupled CL-flow-injection analysis method, tiopronin and its metabolite 2-mercaptopropionic acid in human urine were sensitively determined with the detection limits of 0.8 and 1 pM, respectively [32],... 

Asymmetric alkylation. Deprotonation of (-)-l provides exclusively an (E)-enolate, which is alkylated to provide a single diastereomeric product. De-complexation by oxidation [Br, I2, Ce(IV)] in the presence of water provides the corresponding acid with the same configuration. This sequence has been used for synthesis of the drug (- )-captopril (3). In this case liberation of the acyl group in the presence of the amine provides the amide 2. 

FIGURE 4.90 Oxidation pathways of thiols. In vivo the major product is a mixed disulfide as shown for captopril. 

A FIA method for the determination of captopril was based on the oxidation of the thiol group in the molecule by Ce . This reaction results in the emission of light (chemiluminescence), which can be measured. In this example the dye rhodamine G was used to enhance the emission of light by the reaction. The method developed was rapid and precise. ... 

Captopril degradation is a good example of oxidation of thiols, a reaction very common in protein chemistry (61). 

Aqueous solutions of captopril are prone to oxidative degradation this increases with an increase in pH above 4. There are reports of variations in stability of captopril solutions, depending on the formulation. Addition of sodium ascorbate increases stability of the aqueous solution made of captopril powder. 

Ali SM, Laping NJ, Fredrickson TA et al. (1998) Angiotensinconverting enzyme inhibition attenuates proteinuria and renal TGFpimRNA expression in rats with chronic renal disease. Pharmacology 57 20-27 Ashab I, Peer G, Blum M et al. (1995) Oral administration of L-arginine and captopril in rats prevents chronic renal failure by nitric oxide production. Kidney Int 47 1515-1521 Bardoux P, Martin H, Ahoulay M et al. (1999) Vasopressin contributes to hyperfiltration, albuminuria, and renal hypertrophy in diabetes mellitus Study in vasopressin-deficient Brattleboro rats. Proc Natl Acad Sci USA 96 10397-10402... 

R)-3-Hydroxy-2-methyl propionic acid, an important building block for the synthesis of the widely used antihypertensive drug captopril, was obtained with 97% enantiomeric excess (e.e.) and 100% molar conversion by microbial oxidation of prochiral 2-methyl -1,3-propandiol with Acetobacter pasteurianus [25]. 

The cost of a material is determined in part by the market demand. For instance, triphenylphosphine is a widely used reagent and is much less expensive than its by-product triphenylphosphine oxide, which has fewer synthetic applications. The cost of starting materials for captopril (Figure 2.2) dropped as the cap-topril sales reached 1.5 billion per year. The overall development cost of a drug can decrease markedly if process research and development begins with the most appropriate, inexpensive starting material. 

J.A.M. Pulgarm, L.F.G. Bermejo, P.F. Lopez, Sensitive determination of captopril by time-resolved chemiluminescence using the stopped-flow analysis based on potassium permanganate oxidation, Anal. Chim. Acta 546 (2005) 60. 

X.W. Zheng, Z.J. Zhang, B.X. Li, Flow injection chemiluminescence determination of captopril with in situ electrogenerated Mn if as the oxidant, Electroanal. 13 (2001) 1046. 

Sample preparation 5 mL Urine + 2 mL 500 mM pH 7.0 phosphate buffer -I- 0.5 mL 20 mg/mL p-bromophenaaqueous layer and add it to 100 p-L 2% tributylphosphine in MeOH, heat at 50°for 30 min, wash with 6 mL hexane, add 200 p,L 0.2% N-(4-dimethylamino-3,5-dinitrophenyDmaleimide in acetone to the aqueous layer, mix, let stand at room temperature for 5 min, wash with 6 mL hexane, discard the hexane layer, acidify the aqueous layer with about 200 pL 2 M HCl, extract twice with 6 mL portioiis of benzene (Caution Benzene is a ceircmogen ). Combine the organic layers and add 10 pg IS, evaporate to dryness imder reduced pressure, reconstitute the residue in 200 pL MeOH, inject a 5-20 pL aliquot. (Free captopril is derivatized as its p-bromophenaQrl bromide adduct then oxidized captopril is reduced and derivatized as its N-(4-dimethylamino-3,5-dinitro-phenyl)maleimide adduct.)... 

Retention time 7 (free captopril (as p-bromophena[Pg.222]

Kalia, K. Narula, G.D. Kannan, G.M. Flora, S.J.S. Effects of combined administration of captopril and DMSA on arsenite induced oxidative stress and blood and tissue arsenic concentration in rats. Comp. Biochem. Physiol. C. Toxicol. Pharmacol. 2007,144 (4), 372-379. 

Free thiol groups react with cysteinyl-disulfide residues in proteins to form a new disulfide link with the concomitant release of a free cysteine residue within the protein (Scheme 12, pathway A). No metabolic activation is required for the covalent binding process to occur. Thiols are also readily oxidized to sulfenic acids, which react with cysteinyl residues and reduced GSH to form mixed disulfides (Scheme 12, pathway B) (Migdalof et al., 1984 Coleman et al., 1988). Methimazole, penicillamine, and captopril are examples of free thiol-containing drugs wherein evidence has been presented that traces toxicity of these compounds with oxidation of the thiol group. 

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