Therapeutic androgen receptor ligands

Abstract

In the past several years, the concept of tissue-selective nuclear receptor ligands has emerged. This concept has come to fruition with estrogens, with the successful marketing of drugs such as raloxifene.The discovery of raloxifene and other selective estrogen receptor modulators (SERMs) has raised the possibility of generating selective compounds for other pathways, including androgens (that is, selective androgen receptor modulators, or SARMs).

Design, Synthesis, and in Vivo SAR of a Novel Series of Pyrazolines as Potent Selective Androgen Receptor Modulators

“…Interestingly, 10b was obtained as a pair of diastereomers with the structure similar to the [4,5]-pyrazoline 11. Because of the acid-catalyzed isomerization process of 11 to 7, we decided to carry over 10b directly into biological evaluation without transforming it into the [3,4]-pyrazoline isomer. Thioanilide 10c was obtained by treatment of 7c with Lawesson's reagent.…”

“…Yield, 65%. 1 3.38 (abq, J ) 12.5 Hz, 2H), 2.18 (s, 3H), 1.48 (s, 3H). MS (m/z): 464, (M + H) + , 486 (M + Na) + .…”

“…Yield, 78%. 1 H NMR (CDCl 3 ) δ 9.62 (s, 1H), 8.10 (s, 1H), 7.95 (d, J ) 6.5 Hz, 1H), 7.77 (d, J ) 6.5 Hz, 1H), 6.88 (s, 1H), 5.52 (s, 1H), 3.05 (abq, J ) 12.5 Hz, 2H), 1.56 (s, 3H). MS (m/z): 297, (M + H) + .…”

“…4-dihydro-2H-pyrazole-3-carboxylic acid (4-cyano-3-trifluoromethyl-phenyl)-amide 7c (400 mg, 1.1 mmol) and Na 2 HPO 4 (1.0 g, 7 mmol) in CH 2 Cl 2 (10 mL) was treated with Et 3 O + BF 4 -(1 M in CH 2 Cl 2 , 5.0 mL) at 0°C. The reaction mixture was warmed up to r.t. and stirred overnight and then quenched with NaHCO 3 . CH 2 Cl 2 was added to extract the product, and organic layers were washed with brine and dried over Na 2 SO 4 .…”

“…However, a more widely accepted use of androgen therapy has been hampered by the lack of orally active steroidal preparations with good efficacy and particularly a safe profile for steroidal AR ligands. 3 Efforts to identify more receptor-and tissue-selective ligands without steroid-related side effects and toxicities have shifted focus away from steroid structural templates. Progress has been made over the last 5 years in developing nonsteroidal small molecules that could separate androgenic activities from desirable anabolic activities with improved oral bioavailability and less hepatic toxicity.…”