[2.2.1]-Bicyclic sultams as potent androgen receptor antagonists.

This letter describes the discovery, synthesis, SAR, and biological activity of [2.2.1]-bicyclic sultams as potent antagonists of the androgen receptor. Optimization of the series led to the identification of compound 25, which displayed robust pharmacodynamic effects in rats after oral dosing.

Discovery of the Selective CYP17A1 Lyase Inhibitor BMS-351 for the Treatment of Prostate Cancer.

Efforts to identify a potent, reversible, nonsteroidal CYP17A1 lyase inhibitor with good selectivity over CYP17A1 hydroxylase and CYPs 11B1 and 21A2 for the treatment of castration-resistant prostate cancer (CRPC) culminated in the discovery of BMS-351 (compound 18), a pyridyl biaryl benzimidazole with an excellent in vivo profile. Biological evaluation of BMS-351 at a dose of 1.5 mg in castrated cynomolgus monkeys revealed a remarkable reduction in testosterone levels with minimal glucocorticoid and mineralcorticoid perturbation. Based on a favorable profile, BMS-351 was selected as a candidate for further preclinical evaluation.

Design and synthesis of 4-[3,5-dioxo-11-oxa-4,9-diazatricyclo[5.3.1.0(2,6)]undec-4-yl]-2-trifluoromethyl-benzonitriles as androgen receptor antagonists.

A novel series of 4-[3,5-dioxo-11-oxa-4,9-diazatricyclo[5.3.1.0(2,6)]undec-4-yl]-2-trifluoromethyl-benzonitriles has been synthesized. The ability of these compounds to act as antagonists of the androgen receptor was investigated and several were found to have potent activity in vitro and in vivo.

Discovery of BMS-641988, a novel and potent inhibitor of androgen receptor signaling for the treatment of prostate cancer.

Despite an excellent initial response to first-line hormonal treatment, most patients with metastatic prostate cancer will succumb to a hormone-refractory form of the disease. Because these tumors are still dependent on a functional androgen receptor (AR), there is a need to find novel and more potent antiandrogens. While searching for small molecules that bind to the AR and inhibit its transcriptional activity, BMS-641988 was discovered. This novel antiandrogen showed an increased (>1 log) potency compared with the standard antiandrogen, bicalutamide, in both binding affinity to the AR and inhibition of AR-mediated transactivation in cell-based reporter assays. In mature rats, BMS-641988 strongly inhibited androgen-dependent growth of the ventral prostate and seminal vesicles. In the CWR-22-BMSLD1 human prostate cancer xenograft model, BMS-641988 showed increased efficacy over bicalutamide (average percent tumor growth inhibition >90% versus <50%), even at exposure levels of bicalutamide 3-fold greater than what can be attained in humans. Furthermore, BMS-641988 was efficacious in CWR-22-BMSLD1 tumors initially refractory to treatment with bicalutamide. BMS-641988 was highly efficacious in the LuCaP 23.1 human prostate xenograft model, inducing stasis throughout the approximately 30-day dosing. To explore the functional mechanisms of BMS-641988, gene expression profiling analysis was done on CWR-22-BMSLD1 xenograft models in mice. Treatment with BMS-641988 resulted in a global gene expression profile more similar to castration compared with that of bicalutamide. Overall, these data highlight that the unique preclinical profile of BMS-641988 may provide additional understanding for the hormonal treatment of prostate cancer.

Identification and optimization of a novel series of [2.2.1]-oxabicyclo imide-based androgen receptor antagonists.

A novel series of [2.2.1]-oxabicyclo imide-based compounds were identified as potent antagonists of the androgen receptor. Molecular modeling and iterative drug design were applied to optimize this series. The lead compound [3aS-(3aalpha,4beta,5beta,7beta,7aalpha)]-4-(octahydro-5-hydroxy-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-iodobenzonitrile was shown to have potent in vivo efficacy after oral dosing in the CWR22 human prostate tumor xenograph model.

The androgen receptor can signal through Wnt/beta-Catenin in prostate cancer cells as an adaptation mechanism to castration levels of androgens.

BACKGROUND: A crucial event in Prostate Cancer progression is the conversion from a hormone-sensitive to a hormone-refractory disease state. Correlating with this transition, androgen receptor (AR) amplification and mutations are often observed in patients failing hormonal ablation therapies. beta-Catenin, an essential component of the canonical Wnt signaling pathway, was shown to be a coactivator of the AR signaling in the presence of androgens. However, it is not yet clear what effect the increased levels of the AR could have on the Wnt signaling pathway in these hormone-refractory prostate cells. RESULTS: Transient transfections of several human prostate cancer cell lines with the AR and multiple components of the Wnt signaling pathway demonstrate that the AR overexpression can potentiate the transcriptional activities of Wnt/beta-Catenin signaling. In addition, the simultaneous activation of the Wnt signaling pathway and overexpression of the AR promote prostate cancer cell growth and transformation at castration levels of androgens. Interestingly, the presence of physiological levels of androgen or other AR agonists inhibits these effects. These observations are consistent with the nuclear co-localization of the AR and beta-Catenin shown by immunohistochemistry in human prostate cancer samples. Furthermore, chromatin immunoprecipitation assays showed that Wnt3A can recruit the AR to the promoter regions of Myc and Cyclin D1, which are well-characterized downstream targets of the Wnt signalling pathway. The same assays demonstrated that the AR and beta-Catenin can be recruited to the promoter and enhancer regions of a known AR target gene PSA upon Wnt signaling. These results suggest that the AR is promoting Wnt signaling at the chromatin level. CONCLUSION: Our findings suggest that the AR signaling through the Wnt/beta-Catenin pathway should be added to the well established functional interactions between both pathways. Moreover, our data show that via this interaction the AR could promote prostate cell malignancy in a ligand-independent manner.

Identification of novel functional inhibitors of 17beta-hydroxysteroid dehydrogenase type III (17beta-HSD3).

BACKGROUND: Endocrine therapy of prostate cancer (PCa) relies on agents which disrupt the biosynthesis of testosterone in the testis and/or by direct antagonism of active hormone on the androgen receptor (AR) in non-gonadal target tissues of hormone action such as the prostate. METHODS: In an effort to evaluate new therapies which could inhibit gonadal or non-gonadal testosterone biosynthesis, we developed high throughput biochemical and cellular screening assays to identify inhibitors of 17beta-hydroxysteroid dehydrogenase type III (17beta-HSD3), the enzyme catalyzing the conversion of androstenedione (AdT) to testosterone. RESULTS: Initial screening efforts identified a natural product, 18beta-glycyrrhetinic acid, and a novel derivative of AdT, 3-O-benzylandrosterone, as potent inhibitors of the enzyme. Further efforts led to the identification of several classes of non-steroidal, low molecular weight compounds that potently inhibited 17beta-HSD3 enzymatic activity. One of the most potent classes of 17beta-HSD3 inhibitors was a series of anthranilamide small molecules identified from a collection of compounds related to non-steroidal modulators of nuclear hormone receptors. The anthranilamide based 17beta-HSD3 inhibitors were exemplified by BMS-856, a compound displaying low nanomolar inhibition of 17beta-HSD3 enzymatic activity. In addition, this series of compounds displayed potent inhibition of 17beta-HSD3-mediated cellular conversion of AdT to testosterone and inhibited the 17beta-HSD3-mediated conversion of testosterone necessary to promote AR-dependent transcription. CONCLUSIONS: The identification of non-steroidal functional inhibitors of 17beta-HSD3 may be a useful complementary approach for the disruption of testosterone biosynthesis in the treatment of PCa.

Identification of a novel class of androgen receptor antagonists based on the bicyclic-1H-isoindole-1,3(2H)-dione nucleus.

A novel series of isoindoledione based compounds were identified as potent antagonists of the androgen receptor (AR). SAR around this series revealed dramatic differences in binding and function in mutant variants (MT) of the AR as compared to the wild type (WT) receptor. Optimization of the aniline portion revealed substitution patterns, which yielded potent antagonist activity against the WT AR as well as the MT AR found in the LNCaP and PCa2b human prostate tumor cell lines.

Structure based approach to the design of bicyclic-1H-isoindole-1,3(2H)-dione based androgen receptor antagonists.

A novel series of isoindoledione based compounds were identified as potent antagonists of the androgen receptor (AR). Co-crystallization of members of this family of inhibitors was successfully accomplished with the T877A AR LBD. A working model of how this class of compounds functions to antagonize the AR was created. Based on this model, it was proposed that expanding the bicyclic portion of the molecule should result in analogs which function as effective antagonists against a variety of AR isoforms. In contrast to what was predicted by the model, SAR around this new series was dictated by the aniline portion rather than the bicyclic portion of the molecule.

The synthesis and evaluation of [2.2.1]-bicycloazahydantoins as androgen receptor antagonists.

A novel series of [2.2.1]-azahydantoins has been designed and synthesized in an enantiospecific manner. The ability of these compounds to act as antagonists to the androgen receptor was investigated and several were found to have potent activity in vitro.