4QL8

Crystal structure of Androgen Receptor in complex with the ligand

Summary for 4QL8

• Entry DOI: 10.2210/pdb4ql8/pdb
• Descriptor: 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)
• Functional Keywords: transcription regulation, receptor, transcription
• Biological source: Homo sapiens (human)
• Cellular location: Nucleus: P10275
• Total number of polymer chains: 1
• Total formula weight: 30456.98

Authors

Krishnamurthy, N.,Sangeetha, R.,Ghadiyaram, C.,Sasmal, S.,Subramanya, H.S. (deposition date: 2014-06-11, release date: 2015-06-17, Last modification date: 2023-11-08)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.1 Å)