Synthesis and Biological Activity of a Novel Series of Nonsteroidal, Peripherally Selective Androgen Receptor Antagonists Derived from 1,2-Dihydropyridono[5,6-g]quinolines

Abstract

A new nonsteroidal antiandrogenic pharmacophore has been discovered using cell-based cotransfection assays with human androgen receptor (hAR). This series of AR antagonists is structurally characterized by a linear tricyclic 1,2-dihydropyridono[5,6-g]quinoline core. Analogues inhibit AR-mediated reporter gene expression and bind to AR as potently as or better than any known AR antagonists. Several analogues also showed excellent in vivo activity in classic rodent models of AR antagonism, inhibiting growth of rat ventral prostate and seminal vesicles, without accompanying increases in serum gonadotropin and testosterone levels, as is seen with other AR antagonists. Investigations of structure-activity relationships surrounding this pharmacophore resulted in molecules with complete specificity for AR, antagonist activity on an AR mutant commonly observed in prostate cancer patients, and improved in vivo efficacy. Molecules based on this series of compounds have the potential to provide unique and effective clinical opportunities for treatment of prostate cancer and other androgen-dependent diseases.

Pharmacokinetics and Pharmacodynamics of Nonsteroidal Androgen Receptor Ligands

“…In intact male rats, lead compound LG120907 {1,2,3,4-tetrahydro-2,2-dimethyl-6-trifluoromethyl-8-pyridono [5,6-g]quinoline} showed antagonist activity in the prostate and seminal vesicle without raising the plasma levels of LH and testosterone (45). Compound LG105 {7-fluoro-1,2,3,4-tetra-hydro-2,2-dimethyl-6-trifluoromethyl-8-pyridono [5,6-g]quinoline} also binds to the AR with high affinity (Table II), and demonstrated strong antagonist activity in the prostate, which seemed to be more potent than LG120907.…”

Selective Androgen Receptor Modulators in Drug Discovery: Medicinal Chemistry and Therapeutic Potential

“…7). Initial SAR studies around this template led to improvements in AR antagonist potency and selectivity [45]. Several members of this chemical series demonstrated oral activity, with efficacy superior to flutamide in animal models (analog 15, Fig.…”

Potent, nonsteroidal selective androgen receptor modulators (SARMs) based on 8H-[1,4]oxazino[2,3-f]quinolin-8-ones

“…16 In no instance was agonist activity detected for PR, GR, or MR. No MR antagonist activity was detected, while weak PR and GR antagonist activity is observed (Table 2).…”

“…16 Both R 1 and R 2 positions are important for AR agonist activity as compounds with no R 1 substitutuent showed no agonist activity regardless of the R 2 substituent (Table 1). Antagonist activity was observed (16a-e), demonstrating that this position can be used to switch the AR activity to antagonists.…”