Discovery and design of retinoic acid receptor and retinoid X receptor class- and subtype-selective synthetic analogs of all-trans-retinoic acid and 9-cis-retinoic acid.

This review presents a historical overview of the discoveries of retinoic acid receptor (RAR) and retinoid X receptor (RXR) class- and subtype-selective synthetic retinoids. These synthetic retinoids are conformationally restricted by having aromatic rings in place of the tetraene bond systems of all-trans- and 9-cis-retinoic acids. Events leading to the design and synthesis of such retinoid transcriptional agonists as RAR subtype beta,gamma-selective 6-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-2-naph-thalenecarboxylic acid (TTNN), the RARgamma-selective Z-oxime of 6-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenylcarbonyl)-2-naphthalenecarboxylic acid (SR11254), RAR-selective 4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-anthracenyl) benzoic acid (TTAB), RXR-selective 4-[1-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-cyclopropyl] benzoic acid (SR11246), RXR-selective 4-[1-(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenyl)-2-methylpropenyl]benzoic acid (SR11345), and RARgamma-selective retinoid transcriptional antagonist 2-(6-carboxy-2-naphthalenyl)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-1,3-dithiolane (SR11253) are described.

Topical tretinoin research: an historical perspective.

The topical tretinoin epoch began almost 30 years ago in the laboratories of Stüttgen where he first recognized that a vitamin A derivative, tretinoin, had the potential to be a truly significant form of dermatological therapy. His early clinical trials in a variety of skin disorders provided the first indication of topical activity for the retinoids. Kligman evaluated further the utility of topical tretinoin; focusing his attention on acne. Through these initial studies, topical tretinoin became a fundamental treatment modality for acne. Soon after topical tretinoin was made available, elderly patients using it to treat acne noted a general improvement in the quality of their skin. Kligman began open clinical trials to investigate the effects of topical tretinoin on treatment of photodamaged skin. Positive findings from these trials led to double-blind, vehicle-controlled pilot studies which supported the concept that topical tretinoin could improve the fine wrinkling, mottled hyperpigmentation and tactile roughness which are characteristic of photodamaged skin. These results were verified in two large double-blind, multicentre studies of approximately 700 patients that used not only clinical and patient evaluations but also biopsies and skin surface replicas.

Historical perspectives of tretinoin.

The vitamin A acid story began when topical application of vitamin A (retinol) produced no therapeutic results in dyskeratotic conditions. It was logical to try metabolites of retinol topically. I published results of studies in 1962 that showed that topical tretinoin was beneficial in ichthyosis, actinic keratoses, and other hyperkeratotic conditions. It was reported in 1969 that topical tretinoin was effective in acne vulgaris, principally by preventing and dislodging comedones. It was subsequently demonstrated that tretinoin produced a distinctive kind of hyperplasia of human epidermis that was associated with early shedding of horny cells. Knowledge that the keratinization process was being profoundly altered stimulated interest in synthesizing retinol derivatives (retinoids) that could be administered orally. The development of 13-cis-retinoic acid was an outcome of this interest, a compound that astonished dermatologists by often producing permanent clearing of acne conglobata. The antitumor effects of tretinoin were already demonstrated by 1974, when it was shown to cause regression in many basal cell cancers. Today the cancer chemopreventive capability of retinoids is being intensively investigated in various organs. An international symposium held in Flims, Switzerland in 1975 demonstrated keen awareness of the therapeutic potential of tretinoin and the rapid growth of basic knowledge of the pharmacology of retinoids. From extensive clinical experience new applications for topical tretinoin came to light, ranging from the treatment of flat warts, lichen planus, and Darier's disease, and most recently in retarding photoaging. Perhaps for the first time in history, dermatologists can take credit for pioneering a drug development program that has had a profound influence on medical practice.