维甲酸受体相关孤儿受体C2强效口服生物可利用反向激动剂的发现
Discovery of Potent and Orally Bioavailable Inverse Agonists of the Retinoic Acid Receptor-Related Orphan Receptor C2.
作者信息
von Berg Stefan, Xue Yafeng, Collins Mia, Llinas Antonio, Olsson Roine I, Halvarsson Torbjörn, Lindskog Maria, Malmberg Jesper, Jirholt Johan, Krutrök Nina, Ramnegård Marie, Brännström Marie, Lundqvist Anders, Lepistö Matti, Aagaard Anna, McPheat Jane, Hansson Eva L, Chen Rongfeng, Xiong Yao, Hansson Thomas G, Narjes Frank
机构信息
Medicinal Chemistry, DMPK, andBioscience, Research and Early Development, Respiratory, Inflammation and Autoimmune, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, SE-43183 Mölndal, Sweden.
Structure, Biophysics & FBLG and Mechanistic Biology and Profiling, Discovery Sciences, R&D, AstraZeneca, Gothenburg, SE-43183 Mölndal, Sweden.
出版信息
ACS Med Chem Lett. 2019 May 29;10(6):972-977. doi: 10.1021/acsmedchemlett.9b00158. eCollection 2019 Jun 13.
The further optimization of a recently disclosed series of inverse agonists of the nuclear receptor RORC2 is described. Investigations into the left-hand side of compound , guided by X-ray crystal structures, led to the substitution of the 4-aryl-thiophenyl residue with the hexafluoro-2-phenyl-propan-2-ol moiety. This change resulted in to compound , which combined improved drug-like properties with good cell potency and a significantly lower dose, using an early dose to man prediction. Target engagement was demonstrated in the thymus of mice by a reduction in the number of double positive T cells after oral dosing.
描述了对最近公开的一系列核受体RORC2反向激动剂的进一步优化。在X射线晶体结构的指导下，对化合物左侧进行研究，导致用六氟-2-苯基-丙-2-醇部分取代4-芳基-噻吩基残基。这一变化产生了化合物，该化合物结合了改善的类药性质、良好的细胞活性以及显著更低的剂量（使用早期人体剂量预测）。口服给药后，小鼠胸腺中双阳性T细胞数量减少，证明了靶点结合。
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