ABSTRACT
A novel selective androgen receptor modulator scaffold has been discovered through structural modifications of hydantoin antiandrogens. Several 4-(4-hydroxyphenyl)-N-arylhydantoins displayed partial agonism with nanomolar in vitro potency in transactivation experiments using androgen receptor (AR) transfected cells. In a standard castrated male rat model, several compounds showed good anabolic activity on levator ani muscle, dissociated from the androgenic activity on ventral prostate, after oral dosing at 30 mg/kg. (+)-4-[3,4-Dimethyl-2,5-dioxo-4-(4-hydroxyphenyl)imidazolidin-1-yl]-2-(trifluoromethyl)benzonitrile ((+)-11b) displayed anabolic potency with a strong dissociation between levator ani muscle and ventral prostate (A(50) = 0.5 mg/kg vs 70 mg/kg). The binding modes of two compounds, including (+)-11b, within the AR ligand-binding domain have been studied by cocrystallization experiments using a coactivator-like peptide. Both compounds bound to the same site, and the overall structures of the AR were very similar.
Subject(s)
Androgens/chemical synthesis , Hydantoins/chemical synthesis , Anabolic Agents/chemical synthesis , Anabolic Agents/chemistry , Anabolic Agents/pharmacology , Androgen Receptor Antagonists/chemical synthesis , Androgen Receptor Antagonists/chemistry , Androgen Receptor Antagonists/pharmacology , Androgens/chemistry , Androgens/pharmacology , Animals , Binding, Competitive , Bone and Bones/drug effects , Bone and Bones/physiology , Crystallography, X-Ray , Drug Partial Agonism , HeLa Cells , Humans , Hydantoins/chemistry , Hydantoins/pharmacology , Male , Models, Molecular , Muscle, Skeletal/drug effects , Muscle, Skeletal/metabolism , Orchiectomy , Prostate/drug effects , Prostate/physiology , Rats , Receptors, Androgen/genetics , Receptors, Androgen/metabolism , Stereoisomerism , Structure-Activity Relationship , Transcriptional Activation/drug effectsABSTRACT
Pharmaceutical products, including capsules, oral suspensions, and solutions, are prepared by hospital pharmacists if no commercial product is available. Identification of the raw materials is a regulatory requirement before manufacturing (compounding). Because of the standard methods used, however, this is often time-consuming and laborious in a hospital setting. This article describes the use of near infrared spectroscopy in combination with chemometric methods for discrimination of raw materials. Sixty-three pulverized powder samples were discriminated by using reference samples (identity guaranteed by supplier and confirmed by mid infrared analyses) and NIRCal cluster analyses. A routine expert application involving optimized calibrations (n=6) was developed, which allowed a rapid and nondestructive release procedure for every powder-based raw material received. This technique is superior to established identification analyses because of reduced quarantine times and cost savings.
ABSTRACT
The ligand-binding domain of the human androgen receptor has been cloned, overproduced and crystallized in the presence of a coactivator-like 11-mer peptide and two different nonsteroidal ligands. The crystals of the two ternary complexes were isomorphous and belonged to space group P2(1)2(1)2(1), with one molecule in the asymmetric unit. They diffracted to 1.7 and 1.95 A resolution, respectively. Structure determination of these two complexes will help in understanding the mode of binding of selective nonsteroidal androgens versus endogenous steroidal ligands and possibly the origin of their tissue selectivity.
