Use of RAR Antagonists as Modulators of Hormone Mediated Processes
Inventors: Ron Evans, Laszlo Nagy, and Peter Tontonoz
Potential Uses: Cardiovascular, Obesity. Drug Discovery and Development
RAR Antagonists are capable of modulating processes mediated by other members of the steroid/thyroid hormone receptor superfamily, including permissive receptors such as PPARs.
Retinoic acid receptor (RAR) antagonists are capable of modulating processes mediated by non-RAR members of the steroid/thyroid hormone receptor superfamily including permissive receptors such as PPARs (e.g., PPAR-alpha, PPAR-delta and PPAR-gamma). It has been discovered that RAR antagonists, in combination with agonists for members of the steroid/thyroid hormone receptor superfamily, are capable of inducing and/or enhancing processes mediated by such members. Such compositions will modulate the activity of permissive heterodimers. Permissive heterodimeric members of the steriod/thyroid hormone receptor superfamily include PPAR:RXR, LXR:RXR, NGFI-B:RXR, NURR1:RXR, FXR:RXR, BXR:RXR, SXR:RXR. For example, PPAR regulates genes involved in fatty acid degradation. This is blocked by retinoid agonists. In contrast, an RAR antagonist can stimulate PPAR signalling. Accordingly, a composition composed of an RAR antagonist and a PPAR agonist could represent a unique approach to treat PPAR controlled syndromes such as cardiovascular disease, hyperlipidemia, obesity or insulin resistance which are characterized by altered levels of fatty acids or their metabolites.