Design, Synthesis, and Pharmacological Characterization of 4-[4,4-Dimethyl-3-(4-hydroxybutyl)-5-oxo-2-thioxo-1-imidazolidinyl]- 2-iodobenzonitrile as a High-Affinity Nonsteroidal Androgen Receptor Ligand

• Published in: Journal of medicinal chemistry 2000-08, Vol.43 (17), p.3344-3347
• Main Authors: Van Dort, Marcian E, Robins, Diane M, Wayburn, Bess
• Format: Article
• Language: English
• Subjects: Androgens; Animals; Binding, Competitive; Cell Line; Dihydrotestosterone - pharmacology; Drug Design; Imidazoles - chemical synthesis; Imidazoles - chemistry; Imidazoles - metabolism; Imidazoles - pharmacology; In Vitro Techniques; Ligands; Male; Nitriles - chemistry; Nitriles - metabolism; Nitriles - pharmacology; Prostate - metabolism; Radioligand Assay; Rats; Rats, Wistar; Receptors, Androgen - metabolism; Receptors, Androgen - physiology; Thiones - chemical synthesis; Thiones - chemistry; Thiones - metabolism; Thiones - pharmacology; Transcriptional Activation
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm000163y

4-[4,4-Dimethyl-3-(4-hydroxybutyl)-5-oxo-2-thioxo-1-imidazolidinyl]-2-trifluoromethylbenzonitrile (RU 59063) is a prototype of a new class of high-affinity nonsteroidal androgen receptor (AR) ligands. The search for a radioiodinated AR ligand prompted us to synthesize 4-[4,4-dimethyl-3-(4-hydroxybutyl)-5-oxo-2-thioxo-1-imidazolidinyl]-2-iodobenzonitrile (DTIB) wherein the trifluoromethyl group of RU 59063 was substituted with the similarly hydrophobic iodine atom. DTIB displayed subnanomolar binding affinity (K i = 0.71 ± 0.22 nM) for the rat AR in competitive binding assays. Additionally, DTIB demonstrated potent agonist activity, comparable to that of the natural androgen 5α-dihydrotestosterone (DHT), in a cell-based functional assay (cotransfection assay). DTIB represents a new lead for the development of high-affinity radioiodinated AR radioligands.