Institute of Pharmaceutical Chemistry , Goethe University Frankfurt , Max-von-Laue-Str. 9 , D-60438 Frankfurt , Germany.
Project Group Translational Medicine and Pharmacology TMP , Fraunhofer IME , Theodor-Stern-Kai 7 , D-60596 Frankfurt , Germany.
J Med Chem. 2019 Feb 28;62(4):2112-2126. doi: 10.1021/acs.jmedchem.8b01848. Epub 2019 Feb 15.
The fatty acid sensing nuclear receptor families retinoid X receptors (RXRs) and peroxisome proliferator-activated receptors (PPARs) hold therapeutic potential in neurodegeneration. Valuable pleiotropic activities of Wy14,643 in models of such conditions exceed its known PPAR agonistic profile. Here, we characterize the compound as an RXR agonist explaining the pleiotropic effects and report its systematic structure-activity relationship analysis with the discovery of specific molecular determinants driving activity on PPARs and RXRs. We have designed close analogues of the drug comprising selective and dual agonism on RXRs and PPARs that may serve as superior pharmacological tools to study the role and interplay of the nuclear receptors in various pathologies. A systematically optimized high potency RXR agonist revealed activity in vivo and active concentrations in brain. With its lack of RXR/liver X receptor-mediated side effects and superior profile compared to classical rexinoids, it establishes a new class of innovative RXR modulators to overcome key challenges in RXR targeting drug discovery.
脂肪酸感应核受体家族视黄酸 X 受体 (RXR) 和过氧化物酶体增殖物激活受体 (PPAR) 在神经退行性疾病中具有治疗潜力。Wy14,643 在这些疾病模型中的宝贵多效活性超出了其已知的 PPAR 激动作用谱。在这里，我们将该化合物描述为一种 RXR 激动剂，解释了多效性效应，并报告了其系统的结构-活性关系分析，发现了特定的分子决定因素，可驱动对 PPAR 和 RXR 的活性。我们设计了该药物的类似物，对 RXR 和 PPAR 具有选择性和双重激动作用，可能作为研究核受体在各种病理中的作用和相互作用的更优越的药理学工具。一种系统优化的高活性 RXR 激动剂在体内和大脑中显示出活性和有效浓度。与经典视黄醇类似物相比，它缺乏 RXR/肝 X 受体介导的副作用，且具有优越的特性，为克服 RXR 靶向药物发现中的关键挑战建立了一类新的创新 RXR 调节剂。
