Carboxylic Acid Drugs

In summary, (oxodioxolyl)methyl esters of carboxylic acid drugs appear to be generally useful as prodrugs. However, more studies are needed to document the structure-metabolism relationships, the relative contribution of enzymatic vs. nonenzymatic reactions in their in vivo activation, the reasons of some failures, their toxic potential, and their pharmacokinetic behavior in humans. 

H. Bundgaard, N. M. Nielsen, Glycolamide Esters as Novel Biolabile Prodrug Type for Non-Steroidal Anti-Inflammatory Carboxylic Acid Drugs , Int. J. Pharm. 1988, 43, 101-110. 

DiCarlo, F.J. (1990) Structure-activity relationships (SAR) and structure-metabolism relationships (SMR) affecting the teratogenicity of carboxylic acids. Drug Metab. Rev.,... 

Murti, S. K. 1993. On the preparation and characterization of water-soluble choline salts of carboxylic acid drugs, Ph.D. Dissertation, University of Missouri-Kansas City, Kansas City, MO. 

Patel M. S., F. S. Morton, H. Seager, and D. Howard. 1992. Factors affecting the chemical stability of carboxylic acid drugs in enhanced solubility system (ESS) softgel formulations based on polyethylene glycol (PEG).Drug Development and Industrial Pharmacy, 18 1-19. 

A reversed-phase HPLC post-column ion-pair extraction system was developed by Kim and Stewart [71, 72] for the analysis of carboxylic acid drugs and their salts (sodium formate, sodium acetate, 3-bromopropionic acid, 6-aminocaproic acid, 11-bromoundecanoic acid, 1-heptanesulfonic acid, / -n i t rophcny 1 acetic acid, sodium benzoate, sodium salicylate, valproic acid, probenecid, naproxen, ketoprofen, ibuprofen, mefenamic acid, flufenamic acid, and cefuroxime sodium) using a-(3,4-dimethoxy-phenyl)-4,-trimethylammoniummethylcinnamonitrile methosulfate... 

Bundgaard, H., Nielsen, N.M. (1988) Glycolamide esters as a novel biolabile prodrug type for non-steroidal anti-inflammatory carboxylic acid drugs. IntT. J. Pharm. 43(1-2), 101-110. 

Stewart et. al.(21] have shown the usefulness of FI on-line ion-pair extraction in the determination of carboxylic acid drugs, using salicylic acid, valproic acid, and ibuprofen as model drugs. After a comparison of different chromophoric and fluorophoric cationic dyes in chloroform extractant. Gentian Violet was recommended as counterion for spec-trophotometric determination and Acridine Orange was recommended for fluorimetric determination. The system was used for post column detection in HPLC. 

Primary amines and hydrazines are acetylated by cytosolic polymorphic A-acetyltransferases (NATs) that utilize acetyl-CoA as a cofactor (Sim et al., 2008 Makarova, 2008). Some carboxylic acid drugs acylate amino acids through the formation of adenosine 5 -monophosphate (AMP) intermediates that subsequently form acyl CoA intermediates that react with amino acid A-acyltransferases to yield amides (Pearson and Wienkers, 2008 Testa and Kramer, 2008). A few chemical acylations can occur. 

Fluorescent ion-pair reagent for anal, of carboxylic acid drugs. Cryst. (CHCl3/EtOH aq.). Mp 212-215°. 

T artrazine, 4,5-dihydro-5 -oxo-1 -(4-sulfophenyl)-4-[(4-sulfophenyl)azo]-1// -pyrazole-3-carboxylic acid trisodium salt was discovered by Ziegler in 1884 and is used as a dye for wool and silk. It is used as a colour additive in foods, drugs and cosmetics, and is an adsorption-elution indicator for chloride estimations in biochemistry (B-76MI40404). 

The tricyclic antidepressants (as well as, incidentally the antipsychotic drugs) are characterized by a three carbon chain between the ring system and the basic nitrogen. Incorporation of one of those carbon atoms into an additional fused ring is apparently consistent with activity. Preparation of this compound involves first homologation of the side chain. Thus the carboxylic acid 147 is first converted... 

The latter approach is used in the enantioselective determination of a Phase I metabolite of the antihistaminic drug, terfenadine. Terfenadine is metabolized to several Phase I compounds (Fig. 7-13), among which the carboxylic acid MDL 16.455 is an active metabolite for which plasma concentrations must often be determined. Although terfenadine can be separated directly on Chiralpak AD - an amy-lose-based CSP - the adsorption of the metabolite MDL 16.455 is too high to permit adequate resolution. By derivatizing the plasma sample with diazomethane, the carboxylic acid is converted selectively to the methyl ester, which can be separated in the presence of all other plasma compounds on the above-mentioned CSP Chiralpak AD [24] (Fig. 7-14). Recently, MDL 16.455 has been introduced as a new antihistaminic drug, fexofenadine. 

A different task was pursued by the CM of CsA with various maleates 339 [ 148]. The CM demanded in this case the highly active Hoveyda catalyst D, that exhibits potency not reached by the phosphine-containing catalysts C and E. Under the conditions given in Scheme 65, metathesis with maleates 339 led (E)-selectively to the a,/J-unsaturated ester derivatives 340 in high yield. Compounds 340 still demonstrated activity comparable to that of CsA and are thus potential soft drugs via esterase-mediated biotransformation to the corresponding inactive carboxylic acids 341. 

The structural versatility of pseudopoly (amino acids) can be increased further by considering dipeptides as monomeric starting materials as well. In this case polymerizations can be designed that involve one of the amino acid side chains and the C terminus, one of the amino acid side chains and the N terminus, or both of the amino acid side chains as reactive groups. The use of dipeptides as monomers in the manner described above results in the formation of copolymers in which amide bonds and nonamide linkages strictly alternate (Fig. 3). It is noteworthy that these polymers have both an amino function and a carboxylic acid function as pendant chains. This feature should facilitate the attachment of drug molecules or crosslinkers,... 

Carboxylic acid deaminase FDA Food and Drug Administration... 

Figure 4.18 A, separation of antihistanine and decongestant drugs by reversed-phase IPC. Mobile phase nethanol-water (1 1) containing 5 aM hexanesulfonate and 1 % acetic acid at a flow rate of 3 al/nin. B, separation and indirect OV detection of carboxylic acids by reversed-phase IPC. Coaponents 1 acetic acid, 2 = propionic acid, 3 butyric acid, 4 = valeric acid, 5 caproic acid, and S -. systea peak. Mobile phase 0.3 aM l-phenethyl-2-picoliniua in acetate buffer at pH 4.6.

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