PURPOSE: Optimization of the therapeutic ratio of analogs of the topically active 11-cis, 13-cis-12-hydroxymethylretinoic acid, delta-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 delta-lactone 1 possesses unique molecular features responsible for its desirable therapeutic ratio as an antihyperproliferative 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.
PURPOSE: Optimization of the therapeutic ratio of analogs of the topically active 11-cis, 13-cis-12-hydroxymethylretinoic acid, delta-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 delta-lactone 1 possesses unique molecular features responsible for its desirable therapeutic ratio as an antihyperproliferative 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.
Authors: A H Lewin; R R Goehring; F C Zusi; G J Gendimenico; X Nair; G Whitting; P Bouquin; G Tetrault; F I Carroll Journal: Pharm Res Date: 1994-07 Impact factor: 4.200
Authors: B A Pawson; K K Chan; J DeNoble; R J Han; V Piermattie; A C Specian; S Srisethnil; P W Trown; O Bohoslawec; L J Machlin; E Gabriel Journal: J Med Chem Date: 1979-09 Impact factor: 7.446