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

TLDR

The authors designed, synthesized, and in vivo screened a novel pyrazoline series as tissue‑selective androgen receptor modulators. Structure‑activity relationships were explored at the R1–R6 positions, core pyrazoline ring, and anilide linker, and the compounds were evaluated in castrated and intact rats. (S)-7c exhibited potent AR agonist activity, full anabolic effect orally in castrated rats, partial androgenic activity, and antiandrogenic effect on prostate, establishing it as a tissue‑selective nonsteroidal SARM with muscle agonism and mixed prostate activity.

Abstract

A novel series of pyrazolines 2 have been designed, synthesized, and evaluated by in vivo screening as tissue-selective androgen receptor modulators (SARMs). Structure-activity relationships (SAR) were investigated at the R1 to R6 positions as well as the core pyrazoline ring and the anilide linker. Overall, strong electron-withdrawing groups at the R1 and R2 positions and a small group at the R5 and R6 position are optimal for AR agonist activity. The (S)-isomer of 7c exhibits more potent AR agonist activity than the corresponding (R)-isomer. (S)-7c exhibited an overall partial androgenic effect but full anabolic effect via oral administration in castrated rats. It demonstrated a noticeable antiandrogenic effect on prostate in intact rats with endogenous testosterone. Thus, (S)-7c is a tissue-selective nonsteroidal androgen receptor modulator with agonist activity on muscle and mixed agonist and antagonist activity on prostate.