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

Salvati, Mark; Balog, Aaron; Shan, Weifang; Rampulla, Richard; Giese, Soren; Mitt, Tom; Furch, Joseph A.; Vite, Gregory D.; Attar, Ricardo M.; Jure-Kunkel, Maria; Geng, Jieping; Rizzo, Christopher; Gottardis, Marco M.; Krystek, Stanley R.; Gougoutas, Jack Z.; Galella, Michael A.; Obermeier, Mary; Fura, Aberra; Chandrasena, Gamini

doi:10.1016/j.bmcl.2008.02.006

Cited by 30 publications

(26 citation statements)

References 19 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…2A). Thus, this model is appropriate to investigate the antitumor activity of BMS-641988 (10, 30, and 90 mg/kg) compared with bicalutamide (50 and (27). B, fixed ventral prostates were stained for the proliferation marker Ki-67 (arrowheads ) and counterstained with hematoxylin.…”

Section: Resultsmentioning

confidence: 99%

“…However, a large amount of evidence supports the notion that functional AR signaling is required for the growth of castration-resistant prostate cancer and that more potent antiandrogens could address many of the proposed resistance mechanisms (7). In this report, data are presented on the preclinical characterization of BMS-641988, a member of a novel and highly potent series of [2.2.1]-oxobicycloimide-based AR antagonists (27).…”

Section: Discussionmentioning

confidence: 96%

See 1 more Smart Citation

Discovery of BMS-641988, a Novel and Potent Inhibitor of Androgen Receptor Signaling for the Treatment of Prostate Cancer

et al. 2009

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 96%

Discovery of BMS-641988, a Novel and Potent Inhibitor of Androgen Receptor Signaling for the Treatment of Prostate Cancer

et al. 2009

Self Cite

View full text Add to dashboard Cite

show abstract

“…McGinley et al reported identification of bicalutamide derivatives that at a low micromolar concentration show potent activity in suppressing transcriptional activation of the wild type and the W741L and T877A mutated ARs [32]. Several [2.2.1]-oxabicycloimide-based AR antagonists demonstrated significantly improved efficacy relative to the clinically used antiandrogen bicalutamide in the CWR22R human prostate xenograft model [33]. Novel chalcone 17 identified in the present work is notable since it is a pan-antagonist of the Relative luciferase activity was determined by dual luciferase assay kit (Promega), standardized to Renilla luciferase control and normalized to 0.1 nM DHT without test compound.…”

Section: Discussionmentioning

confidence: 97%

Synthesis and in vitro characterization of ionone-based chalcones as novel antiandrogens effective against multiple clinically relevant androgen receptor mutants

Zhou

Geng

2009

Invest New Drugs

View full text Add to dashboard Cite

A crucial event in prostate cancer progression is the transition from a hormone-sensitive to a lethal castration-refractory disease state. The antagonist-to-agonist conversion due to mutation in AR is a critical problem with the current clinically used antiandrogens. We aim to identify novel antiandrogens that remain as a pure antagonist even in the mutated ARs. By synthesizing a series of ionone-based chalcones, we have identified a novel chalcone (17) that is a pan-antagonist of the wild type and the clinically relevant T877A, W741C and H874Y mutated ARs in luciferase reporter assays in PC-3 cells. Further, chalcone 17 demonstrates sub-micromolar to low micromolar antiproliferative activity in LNCaP, MDA-PCa-2b, 22Rv1 and C4-2B prostate cancer cells, all of which express mutated ARs and confer resistance to the current clinically used antiandrogens. The results suggest that chalcone 17 could be a good candidate for further pre-clinical development as a novel antiandrogen for advanced prostate cancer.

show abstract

“…2–4 Subsequent treatment of maleimide 3 with 2,5-dimethylfuran ( 4 ) in toluene at 80 °C gave the exo Diels-Alder adduct 5 in 50% yield. It is well-known that both furan 5, 6 and 2,5-dimethylfuran 7–9 produce exo Diels-Alder adducts with maleimides under elevated temperature conditions, and that an endo product can be produced if the Diels-Alder reaction is done at room temperature and kept in the dark.…”

mentioning

confidence: 99%

Diels–Alder reactions of five-membered heterocycles containing one heteroatom

Ding

Nguyen

Williams

et al. 2014

Tetrahedron Letters

View full text Add to dashboard Cite

Diels-Alder reactions of five-membered heterocycles containing one heteroatom with an N-arylmaleimide were studied. Cycloaddition of 2,5-dimethylfuran (4) with 2-(4-methylphenyl)maleimide (3) in toluene at 60 °C gave bicyclic adduct 5. Cycloadditions of 3 with 2,5-dimethylthiophene (11) and 1,2,5-trimethylpyrrole (14) were also studied. Interestingly, the bicyclic compound 5 cleanly rearranged, with loss of water, when treated with p-toluenesulfonic acid in toluene at 80 °C to give 4,7-dimethyl-2-p-tolylisoindoline-1,3-dione (6).

show abstract

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

Cited by 30 publications

References 19 publications

Discovery of BMS-641988, a Novel and Potent Inhibitor of Androgen Receptor Signaling for the Treatment of Prostate Cancer

Discovery of BMS-641988, a Novel and Potent Inhibitor of Androgen Receptor Signaling for the Treatment of Prostate Cancer

Synthesis and in vitro characterization of ionone-based chalcones as novel antiandrogens effective against multiple clinically relevant androgen receptor mutants

Diels–Alder reactions of five-membered heterocycles containing one heteroatom

Contact Info

Product

Resources

About