Discovery of Potent and Muscle Selective Androgen Receptor Modulators through Scaffold Modifications

• Published in: Journal of medicinal chemistry Vol. 50; no. 13; pp. 3015 - 3025
• Main Authors: Li, James J, Sutton, James C, Nirschl, Alexandra, Zou, Yan, Wang, Haixia, Sun, Chongqing, Pi, Zulan, Johnson, Rebecca, Krystek, Stanley R, Seethala, Ramakrishna, Golla, Rajasree, Sleph, Paul G, Beehler, Blake C, Grover, Gary J, Fura, Aberra, Vyas, Viral P, Li, Cindy Y, Gougoutas, Jack Z, Galella, Michael A, Zahler, Robert, Ostrowski, Jacek, Hamann, Lawrence G
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 28-06-2007
• Subjects: Administration, Oral; Anabolic Agents - chemical synthesis; Anabolic Agents - pharmacokinetics; Anabolic Agents - pharmacology; Animals; Biological and medical sciences; Biological Availability; Crystallography, X-Ray; Half-Life; Imidazoles - chemical synthesis; Imidazoles - pharmacokinetics; Imidazoles - pharmacology; Male; Medical sciences; Models, Molecular; Muscle; Muscle, Skeletal - anatomy & histology; Muscle, Skeletal - drug effects; Orchiectomy; Pharmacology. Drug treatments; Prostate - anatomy & histology; Prostate - drug effects; Pyrroles - chemical synthesis; Pyrroles - pharmacokinetics; Pyrroles - pharmacology; Rats; Receptors, Androgen - metabolism; Stereoisomerism; Structure-Activity Relationship; Nitrile; Rat; Rodentia; Oral administration; Organic chlorine compounds; In vitro; Dose activity relation; In vivo; Vertebrata; Mammalia; Structure activity relation; Animal; Androgen receptor; selective androgen receptor modulator; Benzonitrile derivatives; Muscle; Chemical synthesis; Hormonal receptor
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm070312d

A novel series of imidazolin-2-ones were designed and synthesized as highly potent, orally active and muscle selective androgen receptor modulators (SARMs), with most of the compounds exhibiting low nM in vitro potency in androgen receptor (AR) binding and functional assays. Once daily oral treatment with the lead compound 11a (AR K i = 0.9 nM, EC50 = 1.8 nM) for 14 days induced muscle growth with an ED50 of 0.09 mg/kg, providing approximately 50-fold selectivity over prostate growth in an orchidectomized rat model. Pharmacokinetic studies in rats demonstrated that the lead compound 11a had oral bioavailability of 65% and a plasma half-life of 5.5 h. On the basis of their preclinical profiles, the SARMs in this series are expected to provide beneficial anabolic effects on muscle with minimal androgenic effects on prostate tissue.