4QL8

Crystal structure of Androgen Receptor in complex with the ligand

4QL8 の概要

• エントリーDOI: 10.2210/pdb4ql8/pdb
• 分子名称: Androgen receptor, 2-chloro-4-[(3S,3aS,4S)-4-hydroxy-3-methoxy-3a,4,5,6-tetrahydro-3H-pyrrolo[1,2-b]pyrazol-2-yl]-3-methylbenzonitrile (3 entities in total)
• 機能のキーワード: transcription regulation, receptor, transcription
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Nucleus: P10275
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 30456.98

構造登録者

Krishnamurthy, N.,Sangeetha, R.,Ghadiyaram, C.,Sasmal, S.,Subramanya, H.S. (登録日: 2014-06-11, 公開日: 2015-06-17, 最終更新日: 2023-11-08)

主引用文献

Ullrich, T.,Sasmal, S.,Boorgu, V.,Pasagadi, S.,Cheera, S.,Rajagopalan, S.,Bhumireddy, A.,Shashikumar, D.,Chelur, S.,Belliappa, C.,Pandit, C.,Krishnamurthy, N.,Mukherjee, S.,Ramanathan, A.,Ghadiyaram, C.,Ramachandra, M.,Santos, P.G.,Lagu, B.,Bock, M.G.,Perrone, M.H.,Weiler, S.,Keller, H.
3-alkoxy-pyrrolo[1,2-b]pyrazolines as selective androgen receptor modulators with ideal physicochemical properties for transdermal administration
J.Med.Chem., 57:7396-7411, 2014

PubMed Abstract: We describe the synthesis and characterization of 3-alkoxy-pyrrolo[1,2-b]pyrazolines as novel selective androgen receptor (AR) modulators that possess excellent physicochemical properties for transdermal administration. Compound 26 bound to human AR with an IC50 of 0.7 nM with great selectivity over other nuclear hormone receptors and potently activated AR in a C2C12 muscle cell reporter gene assay with an EC50 of 0.5 nM. It showed high aqueous solubility of 1.3 g/L at pH 7.4, and an in silico model as well as a customized parallel artificial membrane permeability assay indicated good skin permeation. Indeed, when measuring skin permeation through excised human skin, an excellent flux of 2 μg/(cm(2)·h) was determined without any permeation enhancers. In a 2 week Hershberger model using castrated rats, the compound showed dose-dependent effects fully restoring skeletal muscle weight at 0.3 mg/kg/day after subcutaneous administration with high selectivity over prostate stimulation.

PubMed: 25121964
DOI: 10.1021/jm5009049

実験手法

X-RAY DIFFRACTION (2.1 Å)