Neuroscience Drug Discovery Unit, Wolfson Centre for Age-Related Diseases, Guy's Campus, King's College, London SE1 1UL, UK.
Sygnature Discovery Limited, Biocity, Pennyfoot Street, Nottingham NG1 1GF, UK.
Bioorg Med Chem. 2018 Feb 15;26(4):798-814. doi: 10.1016/j.bmc.2017.12.015. Epub 2017 Dec 9.
A ligand-based virtual screening exercise examining likely bioactive conformations of AM 580 (2) and AGN 193836 (3) was used to identify the novel, less lipophilic RARα agonist 4-(3,5-dichloro-4-ethoxybenzamido)benzoic acid 5, which has good selectivity over the RARβ, and RARγ receptors. Analysis of the medicinal chemistry parameters of the 3,5-substituents of derivatives of template 5 enabled us to design a class of drug-like molecules with lower intrinsic clearance and higher oral bioavailability which led to the novel RARα agonist 4-(3-chloro-4-ethoxy-5-isopropoxybenzamido)-2-methylbenzoic acid 56 that has high RARα potency and excellent selectivity versus RARβ (2 orders of magnitude) and RARγ (4 orders of magnitude) at both the human and mouse RAR receptors with improved drug-like properties. This RARα specific agonist 56 has high oral bioavailability (>80%) in both mice and dogs with a good PK profile and was shown to be inactive in cytotoxicity and genotoxicity screens.
基于配体的虚拟筛选研究考察了 AM 580（2）和 AGN 193836（3）可能的生物活性构象，以鉴定新型、亲脂性较低的 RARα激动剂 4-(3,5-二氯-4-乙氧基苯甲酰胺基)苯甲酸 5，其对 RARβ和 RARγ受体具有良好的选择性。对模板 5 的 3,5-取代基的药物化学参数的分析，使我们能够设计出一类具有较低内在清除率和较高口服生物利用度的类药性分子，从而得到新型的 RARα激动剂 4-(3-氯-4-乙氧基-5-异丙氧基苯甲酰胺基)-2-甲基苯甲酸 56，该化合物对人源和鼠源 RARα受体具有高活性和优异的选择性（对 RARβ的选择性为 2 个数量级，对 RARγ的选择性为 4 个数量级），同时具有改善的类药性。该 RARα特异性激动剂 56 在小鼠和狗中具有较高的口服生物利用度（>80%），具有良好的 PK 特征，并在细胞毒性和遗传毒性筛选中显示无活性。
