title: 3-alkoxy-pyrrolo[1,2-b]pyrazolines as selective androgen receptor modulators with ideal physicochemical properties for transdermal administration.
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.
authors.affiliation: Global Discovery Chemistry and #Musculoskeletal Diseases, Novartis Institutes for BioMedical Research , CH-4002 Basel, Switzerland.
authors.forename: Thomas
authors.initials: T
authors.lastname: Ullrich
authors.forename: Sanjita
authors.initials: S
authors.lastname: Sasmal
authors.forename: Venkatesham
authors.initials: V
authors.lastname: Boorgu
authors.forename: Srinivasu
authors.initials: S
authors.lastname: Pasagadi
authors.forename: Srisailam
authors.initials: S
authors.lastname: Cheera
authors.forename: Sujatha
authors.initials: S
authors.lastname: Rajagopalan
authors.forename: Archana
authors.initials: A
authors.lastname: Bhumireddy
authors.forename: Dhanya
authors.initials: D
authors.lastname: Shashikumar
authors.forename: Shekar
authors.initials: S
authors.lastname: Chelur
authors.forename: Charamanna
authors.initials: C
authors.lastname: Belliappa
authors.forename: Chetan
authors.initials: C
authors.lastname: Pandit
authors.forename: Narasimharao
authors.initials: N
authors.lastname: Krishnamurthy
authors.forename: Subhendu
authors.initials: S
authors.lastname: Mukherjee
authors.forename: Anuradha
authors.initials: A
authors.lastname: Ramanathan
authors.forename: Chakshusmathi
authors.initials: C
authors.lastname: Ghadiyaram
authors.forename: Murali
authors.initials: M
authors.lastname: Ramachandra
authors.forename: Paulo G
authors.initials: PG
authors.lastname: Santos
authors.forename: Bharat
authors.initials: B
authors.lastname: Lagu
authors.forename: Mark G
authors.initials: MG
authors.lastname: Bock
authors.forename: Mark H
authors.initials: MH
authors.lastname: Perrone
authors.forename: Sven
authors.initials: S
authors.lastname: Weiler
authors.forename: Hansjoerg
authors.initials: H
authors.lastname: Keller
mesh_terms: D000279:Administration, Cutaneous; D059002:Androgen Receptor Antagonists / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics; D000728:Androgens / Q000737:chemistry* / Q000378:metabolism; D000818:Animals; D019540:Area Under Curve; D053961:Azabicyclo Compounds / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics; D001665:Binding Sites; D001667:Binding, Competitive; D002460:Cell Line; D055598:Chemical Phenomena; D018360:Crystallography, X-Ray; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate; D051379:Mice; D008956:Models, Chemical; D008958:Models, Molecular; D015394:Molecular Structure; D017434:Protein Structure, Tertiary; D011720:Pyrazoles / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics; D017208:Rats, Wistar; D011944:Receptors, Androgen / Q000737:chemistry* / Q000378:metabolism; D012867:Skin / Q000378:metabolism
chemical_list: C000593225:2-chloro-4-(4-hydroxy-3-methoxy-3a,4,5,6-tetrahydro-3H-pyrrolo(1,2-b)pyrazol-2-yl)-3-methylbenzonitrile; C410798:AR protein, human; D059002:Androgen Receptor Antagonists; D000728:Androgens; D053961:Azabicyclo Compounds; D011720:Pyrazoles; D011944:Receptors, Androgen