title: Design, synthesis, and biological evaluation of nonsteroidal cycloalkane[d]isoxazole-containing androgen receptor modulators.
abstract: We report here the design, preparation, and systematic evaluation of a novel cycloalkane[d]isoxazole pharmacophoric fragment-containing androgen receptor (AR) modulators. Cycloalkane[d]isoxazoles form new core structures that interact with the hydrophobic region of the AR ligand-binding domain. To systematize and rationalize the structure-activity relationship of the new fragment, we used molecular modeling to design a molecular library containing over 40 cycloalkane[d]isoxazole derivatives. The most potent compound, 4-(3a,4,5,6,7,7a-hexahydrobenzo[d]isoxazol-3-yl)-2-(trifluoromethyl)benzonitrile (6a), exhibits antiandrogenic activity significantly greater than that of the most widely used antiandrogenic prostate cancer drugs bicalutamide (1) and hydroxyflutamide (2) in reporter gene assays measuring the transcriptional activity of AR (decreasing approximately 90% of the total AR activity) and in competitive AR ligand-binding assays (showing over four times higher potency to inhibit radioligand binding in comparison to bicalutamide). Notably, 6a maintains its antiandrogenic activity with AR mutants W741L and T877A commonly observed and activated by bicalutamide and hydroxyflutamide, respectively, in prostate cancer patients.
authors: School of Pharmacy, University of Eastern Finland, P.O. Box 1627, FI-70211 Kuopio, Finland.
authors: Pekka K
authors: PK
authors: Poutiainen
authors: Tuomas
authors: T
authors: Oravilahti
authors: Mikael
authors: M
authors: Peräkylä
authors: Jorma J
authors: JJ
authors: Palvimo
authors: Janne A
authors: JA
authors: Ihalainen
authors: Reino
authors: R
authors: Laatikainen
authors: Juha T
authors: JT
authors: Pulkkinen
mesh_terms: D000818:Animals; D019556:COS Cells; D060326:Chemistry Techniques, Synthetic; D002522:Chlorocebus aethiops; D003516:Cycloparaffins / Q000737:chemistry*; D015195:Drug Design; D007555:Isoxazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular; D057466:Nonsteroidal Anti-Androgens / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D011487:Protein Conformation; D011944:Receptors, Androgen / Q000737:chemistry / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D003516:Cycloparaffins; D007555:Isoxazoles; D057466:Nonsteroidal Anti-Androgens; D011944:Receptors, Androgen