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. 2010 Apr 8;53(7):2779-96.
doi: 10.1021/jm901488g.

Structure-activity relationship for thiohydantoin androgen receptor antagonists for castration-resistant prostate cancer (CRPC)

Michael E Jung  1 , Samedy Ouk, Dongwon Yoo, Charles L Sawyers, Charlie Chen, Chris Tran, John Wongvipat
Affiliations

Structure-activity relationship for thiohydantoin androgen receptor antagonists for castration-resistant prostate cancer (CRPC)

Michael E Jung et al. J Med Chem. .

Abstract

A structure-activity relationship study was carried out on a series of thiohydantoins and their analogues 14 which led to the discovery of 92 (MDV3100) as the clinical candidate for the treatment of hormone refractory prostate cancer.

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Figures

Figure 1
Figure 1
Fold change in tumor volume of xenografts with bical, 27 and 38 (10 mg/kg)
Figure 2
Figure 2
Dose response in change in tumor volume of xenografts with 38
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Figure 3
Serum concentration of 22 after IV injection n=3 mice
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Figure 4
PK curves of 38 and 80
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Figure 5
Concentration of 91 after IV (blue) or oral (pink) administration
Figure 6
Figure 6
Effect of bicalutamide and 91 on LNCaP/AR (HR) tumor size at 10 and 50 mg/kg once a day
Figure 7
Figure 7
Dose response in tumor volume change of xenografts with 91 at 0.1, 1, and 10 mg/kg once a day
Figure 8
Figure 8
Effect of change in tumor volume of xenografts with 91 at 10 mg/kg once a day
Figure 9
Figure 9
Dose-response study of 91 and 92 (nM) on castration resistant LNCaP AR cells
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Effect of 38, 80, and 91 on hormone sensitive LNCaP cells
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Scheme 21
See this image and copyright information in PMC

References

    1. Feldman BJ, Feldman D. The development of androgen-independent prostate cancer. Nat. Rev. Cancer. 2001;1:34–45. - PubMed
    2. Gelmann EP. Molecular biology of the androgen receptor. J. Clin. Oncol. 2002;20:3001–3015. - PubMed
    3. Balk SP. Androgen receptor as a target in androgen-independent prostate cancer. Urology. 2002;60:132–138. - PubMed
    1. Chen CD, Welsbie DS, Tran C, Baek SH, Chen R, Vessella R, Rosenfeld MG, Sawyers CL. Molecular determinants of resistance to antiandrogen therapy. Nature Med. 2004;10:33–39. - PubMed

    1. Information on the clinical trials of this compound can be obtained at www.clinicaltrials.gov

    1. Tran C, Ouk S, Clegg NJ, Chen Y, Watson PA, Arora V, Wongvipat J, Smith-Jones PM, Yoo D, Kwon A, Wasielewska T, Welsbie D, Chen C, Higano CS, Beer TM, Hung DT, Scher HI, Jung ME, Sawyers CL. Development of a second-generation antiandrogen for treatment of advanced prostate cancer. Science. 2009;324:787–790. - PMC - PubMed
    1. Teutsch G, Goubet F, Battmann T, Bonfils A, Bouchoux F, Cerede E, Gofflo D, Gaillard-Kelly M, Philibert D. Non-steroidal antiandrogens: Synthesis and biological profile of high-affinity ligands for the androgen receptor. J. Steroid Biochem. Molec. Biol. 1994;48:111–119. - PubMed

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