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.
Subject(s)
Androgen Receptor Antagonists/chemistry , Androgens/chemistry , Azabicyclo Compounds/chemistry , Pyrazoles/chemistry , Receptors, Androgen/chemistry , Administration, Cutaneous , Androgen Receptor Antagonists/metabolism , Androgen Receptor Antagonists/pharmacokinetics , Androgens/metabolism , Animals , Area Under Curve , Azabicyclo Compounds/metabolism , Azabicyclo Compounds/pharmacokinetics , Binding Sites , Binding, Competitive , Cell Line , Chemical Phenomena , Crystallography, X-Ray , Humans , Male , Metabolic Clearance Rate , Mice , Models, Chemical , Models, Molecular , Molecular Structure , Protein Structure, Tertiary , Pyrazoles/metabolism , Pyrazoles/pharmacokinetics , Rats, Wistar , Receptors, Androgen/metabolism , Skin/metabolismABSTRACT
RPR127963 demonstrates an excellent pharmacokinetic profile in several species and was found to be efficacious in the prevention of restenosis in a Yucatan mini-pig model upon oral administration of 1-5 mg/kg. The in vitro selectivity profile and SAR of the highly optimized PDGF-R tyrosine kinase inhibitor are highlighted.
