3-Alkoxy-pyrrolo[1,2-b]pyrazolines as Selective Androgen Receptor Modulators with Ideal Physicochemical Properties for Transdermal Administration

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• 作者：Thomas Ullrich ; Sanjita Sasmal ; Venkatesham Boorgu ; Srinivasu Pasagadi ; Srisailam Cheera ; Sujatha Rajagopalan ; Archana Bhumireddy ; Dhanya Shashikumar ; Shekar Chelur ; Charamanna Belliappa ; Chetan Pandit ; Narasimharao Krishnamurthy ; Subhendu Mukherjee ; Anuradha Ramanathan ; Chakshusmathi Ghadiyaram ; Murali Ramachandra ; Paulo G. Santos ; Bharat Lagu ; Mark G. Bock ; Mark H. Perrone ; Sven Weiler ; Hansjoerg Keller
• 刊名：Journal of Medicinal Chemistry
• 出版年：2014
• 出版时间：September 11, 2014
• 年：2014
• 卷：57
• 期：17
• 页码：7396-7411
• 全文大小：569K
• ISSN：1520-4804

文摘

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 渭g/(cm²路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.