ABSTRACT
Structural modification performed on a 4-methyl-4-(4-hydroxyphenyl)hydantoin series is described which resulted in the development of a new series of 4-(hydroxymethyl)diarylhydantoin analogues as potent, partial agonists of the human androgen receptor. This led to the identification of (S)-(-)-4-(4-(hydroxymethyl)-3-methyl-2,5-dioxo-4-phenylimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile ((S)-(-)-18a, GLPG0492) evaluated in vivo in a classical model of orchidectomized rat. In this model, (-)-18a exhibited anabolic activity on muscle, strongly dissociated from the androgenic activity on prostate after oral dosing. (-)-18a has very good pharmacokinetic properties, including bioavailability in rat (F > 50%), and is currently under evaluation in phase I clinical trials.
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 , Biological Availability , Drug Partial Agonism , HeLa Cells , Humans , Hydantoins/chemistry , Hydantoins/pharmacology , Male , Models, Molecular , Molecular Conformation , Muscle, Skeletal/anatomy & histology , Muscle, Skeletal/drug effects , Muscle, Skeletal/metabolism , Orchiectomy , Organ Size/drug effects , Prostate/anatomy & histology , Prostate/drug effects , Prostate/metabolism , Rats , Rats, Sprague-Dawley , Receptors, Androgen/genetics , Receptors, Androgen/metabolism , Stereoisomerism , Structure-Activity Relationship , Transcriptional Activation/drug effectsABSTRACT
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
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.
