Abstract
Purpose. Optimization of the therapeutic ratio of analogs of the topically active 11-cis,13-cis-12-hydroxymethylretinoic acid, δ-lactone (1) relative to antihyperproliferation and antihyperkeratinization vs. toxicity.
Methods. Nine analogs of 1, in which variations were made in the lipophilic cyclohexenyl moiety or in the lactone ring, were evaluated for topical activity against hyperkeratinization, inhibition of TPA-induced DNA synthesis and for skin irritation.
Results. Although more potent lactones than the parent lactone 1 were identified, none possessed the favorable therapeutic ratio associated with 1.
Conclusions. The δ-lactone 1 possesses unique molecular features responsible for its desirable therapeutic ratio as an anti-hyperproliferative and antihyperkeratotic agent. In view of its very low systemic retinoid toxicity and the absence of any systemic toxicity, this lactone may be a good candidate for use in the topical treatment of acne.
Similar content being viewed by others
REFERENCES
L. Packer (Ed.). Methods in Enzymology, Academic Press, Inc., San Diego, California, 1990, Vol. 190.
A.H. Lewin, R.R. Goehring, F.C. Zusi, K.M. Tramposch, X. Nair, G. Whiting, P. Bouquin, G. Tetrault and F.I. Carroll. The requirement for a retinoic acid lactone of 11-cis,13-cis-stereochemistry for topical dermatologic activity. Pharm. Res. 11: 1065–1067 (1994).
A.H. Lewin, M.E. Bos, F.C. Zusi, X. Nair, G. Whiting, P. Bouquin, G. Tetrault and F.I. Carroll. Evaluation of retinoids as therapeutic agents in dermatology. Pharm. Res. 11: 192–200 (1994).
Hoffman-LaRoche & CIE, Substituted phenyl-nona-tetraenic acids esters and amides—for treatment of benign and malignant neoplasm acne and psoriasis, Belgium Patent 813,002 (1974).
A.H. Lewin, S.R. Parker, N.B. Fleming and F.I. Carroll. Formylation of arenes by α,α-dichloromethyl methyl ether. An improved experimental procedure. Org. Prep. Proc. Int. 10: 201–204 (1978).
B.A. Pawson, K.-K. Chan, D. James, R.-J.L. Han, V. Piermattie, A.C. Specian, S. Srisethnil, P.W. Trown, O. Bohoslawec, L.J. Machlin and E. Gabriel. Fluorinated retinoic acids and their analogues. 1. Synthesis and biological activity of (4-methoxy-2,3,6-trimethylphenyl)nonatetraenoic acid analogues. J. Med. Chem. 22: 1059–1067 (1979).
A.H. Lewin, D.H. Rector, S.R. Parker, M.C. Wani and F.I. Carroll. Configurationally locked retinoids. 13-cis-δ-Lactones of 12-carboxyretinol and 12-(hydroxymethyl)retinoic acid. J. Org. Chem. 48: 222–227 (1983).
A.H. Lewin, M.G. Whaley, S.R. Parker, F.I. Carroll and C.G. Moreland. 12-Carboxyretinoic acids. Synthesis and structure. J. Org. Chem. 47: 1799–1807 (1982).
P. Loeliger, W. Bollag and H. Mayer. Arotinoids, a new class of highly active retinoids. Eur. J. Med. Chem.—Chim. Thera. 15: 9–15 (1980).
M.B. Sporn and A.B. Roberts. Biological methods for analysis and assay of retinoids—relationships between structure and activity. In M.B. Sporn, A.B. Roberts and D.S. Goodman (eds.). The Retinoids. Academic Press, Inc., New York and London, 1984, Vol. 1, pp. 235–279.
X. Nair, J. Quigley, K.M. Tramposch, F.I. Carroll, A.H. Lewin and I. Kiss. BMY 30047: A novel topically active retinoid with low local and systemic toxicity. J. Pharmacol. Exp. Ther. 256: 365–370 (1991).
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Lewin, A.H., Black, S.L., Bos, M.E. et al. Evaluation of Retinoid Lactones as Topical Therapeutic Agents in Dermatology. Pharm Res 12, 983–992 (1995). https://doi.org/10.1023/A:1016250129246
Issue Date:
DOI: https://doi.org/10.1023/A:1016250129246