Abstract
A series of novel ω-(N,N,N-trialkylammonium)alkyl ester and thioester derivatives [RCOM(CH2) n NR 3 + X −, M = O or S, n = 2–6, X = I or Cl] of 11 nonsteroidal antiinflammatory carboxylic acid agents (naproxen, ketorolac, indomethacin, ibuprofen, sulindac, ketoprofen, flufenamic acid, mefenamic acid, zomepirac, etodolac, and tifurac) was prepared and evaluated for their antiinflammatory, analgesic, and gastrointestinal erosive properties. In general, each prodrug retained the antiinflammatory activity characteristic of the corresponding parent drug but exhibited moderately to greatly reduced gastrointestinal erosive properties and significantly reduced analgetic potencies. This profile is likely due to a combination of factors including the rate of hydrolysis of the esters in the stomach, gut, and plasma, changes in the locus of absorption of the prodrug or nonsteroidal antiinflammatory drug (NSAID), and altered metabolic disposition patterns resulting from these changes. The results obtained from the compounds of this series indicate that esters of this general class may offer a means to modulate both the aqueous/lipid solubility and the hydrolytic/enzymatic cleavage indices of NSAID prodrugs which potentially possess a more favorable therapeutic ratio of antiinflammatory to gastrointestinal erosive activities.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
REFERENCES
J. G. Lombardino (ed.). Nonsteroidal Antiinflammatory Drugs, Wiley, New York, 1985.
A. Buege. Wiss. Z. Martin Luther Univ. Halle Wittenberg Math.-Naturwiss. Reihe 35:106–118 (1986); Chem. Abstr. 105:90652c (1987).
T.-Y. Shen and C. A. Winter. In N. J. Harper and A. B. Simmonds (eds.), Advances in Drug Research, Vol. 12, Academic Press, New York, 1977, pp. 89–249.
D. C. Schlegel, B. L. Zenitz, C. A. Fellows, S. C. Laskowski, D. C. Behn, D. K. Phillips, I. Botton, and P. T. Speight. J. Med. Chem. 27:1682–1690 (1984).
A. A. Sinkula and S. H. Yalkowsky. J. Pharm. Sci. 64:181–210 (1975).
A. A. Sinkula. Annu. Rep. Med. Chem. 10:306–316 (1975).
V. Stella. In T. Higuchi and V. Stella (eds)., Prodrugs as Novel Drug Delivery Systems, American Chemical Society, Washington, D.C., 1974, pp. 1–115.
H. Bungaard. In E. B. Roche (ed.), Bioreversible Carriers in Drug Design: Theory and Application, Pergamon Press, New York, 1987, pp. 13–94.
N. M. Nielsen and H. Bundgaard. J. Pharm. Sci. 77:285–298 (1988).
P. Stenberg, C. G. Curtis, D. Wing, Y. S. Tong, R. B. Credo, A. Gray, and L. Lorand. Biochem. J. 147:155–163 (1975).
A. Reiner. Eur. Patent Appl. EP 237 495 (1987); Chem. Abstr. 108:111984s (1988).
J. Alexander and J. A. Fix. Eur. Patent Appl. EP 206 947 (1986).
For an excellent review of the laboratory models used to determine NSAID potency, efficacy and safety, see I. G. Otterness and M. L. Bliven. In J. G. Lombardino (ed.), Nonsteroidal Antiinflammatory Drugs, Wiley, New York, 1985, pp. 111–252. The protocols used in this study are adapted from standard methods used in the development of naproxen, ketorolac, and tifurac by the Institute of Biological Sciences, Syntex Research.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Venuti, M.C., Young, J.M., Maloney, P.J. et al. Synthesis and Biological Evaluation of Ω-(N,N,N-Trialkylammonium)alkyl Esters and Thioesters of Carboxylic Acid Nonsteroidal Antiinflammatory Agents. Pharm Res 6, 867–873 (1989). https://doi.org/10.1023/A:1015960522189
Issue Date:
DOI: https://doi.org/10.1023/A:1015960522189