Identification of Novel Steroidal Androgen Receptor Degrading Agents Inspired by Galeterone 3β-Imidazole Carbamate.

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TitleIdentification of Novel Steroidal Androgen Receptor Degrading Agents Inspired by Galeterone 3β-Imidazole Carbamate.
Publication TypeJournal Article
Year of Publication2016
AuthorsPurushottamachar, P, Kwegyir-Afful, AK, Martin, MS, Ramamurthy, VP, Ramalingam, S, Njar, VCO
JournalACS Med Chem Lett
Volume7
Issue7
Pagination708-13
Date Published2016 Jul 14
ISSN1948-5875
Abstract

Degradation of all forms of androgen receptors (ARs) is emerging as an advantageous therapeutic paradigm for the effective treatment of prostate cancer. In continuation of our program to identify and develop improved efficacious novel small-molecule agents designed to disrupt AR signaling through enhanced AR degradation, we have designed, synthesized, and evaluated novel C-3 modified analogues of our phase 3 clinical agent, galeterone (5). Concerns of potential in vivo stability of our recently discovered more efficacious galeterone 3β-imidazole carbamate (6) led to the design and synthesis of new steroidal compounds. Two of the 11 compounds, 3β-pyridyl ether (8) and 3β-imidazole (17) with antiproliferative GI50 values of 3.24 and 2.54 μM against CWR22Rv1 prostate cancer cell, are 2.75- and 3.5-fold superior to 5. In addition, compounds 8 and 17 possess improved (∼4-fold) AR-V7 degrading activities. Importantly, these two compounds are expected to be metabolically stable, making them suitable for further development as new therapeutics against all forms of prostate cancer.

DOI10.1021/acsmedchemlett.6b00137
Alternate JournalACS Med Chem Lett
PubMed ID27437082
PubMed Central IDPMC4948004