Current research and future developments in retinoids: oral and topical agents

The retinoids are a class of small molecules capable of affecting biological systems in a fundamental way by interacting with a variety of nuclear receptors and affecting gene transcription. As such, they have powerful therapeutic potential in the treatment of a variety of diseases. However, non-selective retinoid drugs that indiscriminately activate many or all of the different retinoid receptors and their signaling pathways will invariably produce both undesirable and beneficial effects. Therefore, current and future retinoid research must employ a rational approach to drug discovery, the goal of which is to design retinoid drugs with sufficient receptor or function selectivity that only those biological systems relevant to a specific disease are affected. Tazarotene is a retinoid with properties that are a result of this rational approach to drug discovery. Its molecular structure was engineered in such a way as to make it selective for the retinoic acid receptor (RAR) class of nuclear receptors over retinoid X receptors (RXRs), with preferential activation of RAR beta and RAR gamma over RAR alpha. It was further engineered to possess clinically favorable pharmacokinetic properties. To date, all retinoid drugs available for therapeutic use are retinoid agonists; they bind to retinoid receptors and facilitate gene transcription. However, ongoing research has developed retinoid antagonists (that bind to receptors without activating gene transcription) and inverse agonists (that bind to receptors and inhibit gene transcription). These new drugs and other retinoids currently under development represent new opportunities for the treatment of a variety of disorders in dermatology, oncology, and metabolic disease.