Ullrich, Thomas, Fernandes Gomes Dos Santos, Paulo Antonio, Perrone, Mark, Weiler, Sven, Keller, Hansjoerg, Sasmal, Sanjita, Boorgu, Venkatesham, Pasagadi, Srinivasu, Cheera, Srisailam, Rajagopalan, Sujatha , Bhumireddy, Archana, Shashikumar, Dhanya, Chelur, Shekar, Belliappa, Charamanna, Pandit, Chetan, Krishnamurthy, Narasimharao, Mukherjee, Subhendu, Ramanathan, Anuradha, Ghadiyaram, Chakshusmathi , Ramachandra, Murali, Lagu, Bharat and Bock, Mark G. (2014) 3-Alkoxy-pyrrolo[1,2-b]pyrazolines as novel selective androgen receptor modulators (SARMs) with physicochemical properties suitable for transdermal administration. Journal of Medicinal Chemistry, 57 (17). pp. 7396-7411. ISSN 0022-26231520-4804

Abstract

We describe the synthesis and characterization of 3-alkoxy-pyrrolo[1,2-b]pyrazolines as novel selective androgen receptor (AR) modulators that possess adequate physicochemical properties for transdermal administration. Compound 26 binds to human AR with an IC50 of 0.7 nM with great selectivity over other nuclear hormone receptors and potently activates AR in a C2C12 muscle cell reporter gene assay with an EC50 of 0.5 nM. It showed excellent 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 indicate good skin permeation. Indeed, when measuring skin permeation through excised human skin an excellent flux of 2 µg/(cm2*h) was determined without any permeation enhancers. In a two-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.

Item Type:	Article
Date Deposited:	26 Apr 2016 23:45
Last Modified:	26 Apr 2016 23:45
URI:	https://oak.novartis.com/id/eprint/22128