Identification of a novel series of tetrahydrodibenzazocines as inhibitors of 17β-hydroxysteroid dehydrogenase type 3

Fink, Brian E.; Gavai, Ashvinikumar V.; Tokarski, John S.; Goyal, Bindu; Misra, Raj N.; Xiao, Hai-Yun; Kimball, S. David; Han, Wen-Ching; Norris, Derek; Spires, Thomas E.; You, Dan; Gottardis, Marco M.; Lorenzi, Matthew V.; Vite, Gregory D.

doi:10.1016/j.bmcl.2005.12.039

Cited by 40 publications

(25 citation statements)

References 17 publications

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“…Both Schering-Plough and BMS have reported potent selective non-steroidal inhibitors as promising leads (Guzi et al, 2004;Fink et al, 2006). Based on highly preferred structures from the Schering-Plough patents a pharmacophore was constructed and used in virtual screening of the Maybridge database to discover potential lead templates for further A c c e p t e d M a n u s c r i p t 13 thought to be the aromatic hydrophobic head, a functionalised spacer or linking group and a hydrogen bond acceptor distal from the hydrophobic head.…”

Section: Resultsmentioning

confidence: 99%

“…Recently some potent selective inhibitors have been reported by Schering-Plough and BristolMyers Squibb (BMS) (Fig.1) (Guzi et al, 2004;Fink et al, 2006). Efficacy studies, using SCH-451659, in cynomologus monkeys showed promising results, leading to a 50% reduction in serum testosterone levels, an 85% decrease in testicular testosterone levels and a 20% decrease in prostate weight after 4 weeks dosing at 15 mg/kg, BID, p.o.…”

Section: Page 3 Of 25mentioning

confidence: 99%

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The design of novel 17β-hydroxysteroid dehydrogenase type 3 inhibitors

Vicker

Sharland

Heaton

et al. 2009

Molecular and Cellular Endocrinology

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Abstract17β-hydroxysteroid dehydrogenase type 3 (17β-HSD3) is expressed at high levels in the testes and seminal vesicles but has also been shown to be present in prostate tissue, suggesting its potential involvement in both gonadal and non-gonadal testosterone biosynthesis. The role of 17β-HSD3 in testosterone biosynthesis makes this enzyme an attractive molecular target for inhibition by small molecule inhibitors for the treatment of prostate cancer.Here we report the design of selective inhibitors of 17β-HSD3 as potential anti-cancer agents.Due to 17β-HSD3 being a membrane-bound protein a crystal structure is not yet available. A homology model of 17β-HSD3 has been built to aid structure-based drug design. This model has been used with docking studies to identify a series of lead compounds that may give an insight as to how inhibitors interact with the active site. Compound 1 was identified as a potent selective inhibitor of 17β-HSD3 with an IC 50 = 700 nM resulting in the discovery of a novel lead series for further optimization. Using our homology model as a tool for inhibitor design compound 5 was discovered as a novel potent and selective inhibitor of 17β-HSD3 with an IC 50 ~ 200 nM.

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Section: Resultsmentioning

confidence: 99%

Section: Page 3 Of 25mentioning

confidence: 99%

The design of novel 17β-hydroxysteroid dehydrogenase type 3 inhibitors

Vicker

Sharland

Heaton

et al. 2009

Molecular and Cellular Endocrinology

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“…To aid structure-based drug design, some homology models of HSD17B3 have been developed [78][79][80][81] . A series of compounds based on the dibenzazepine scaffold was discovered in 2006 and compound 29 [ Figure 10] was initially identified as promising hit compound and used as a lead to discover compound 30, which exerted picomolar activity in enzymatic as well as cellular (stably expressing 17β-HSD3 MDA-MB453 cells) assays [78] .…”

Section: Hsd17b3mentioning

confidence: 99%

“…A series of compounds based on the dibenzazepine scaffold was discovered in 2006 and compound 29 [ Figure 10] was initially identified as promising hit compound and used as a lead to discover compound 30, which exerted picomolar activity in enzymatic as well as cellular (stably expressing 17β-HSD3 MDA-MB453 cells) assays [78] . This compound was very useful in helping the design of the subsequently discovered 17β-HSD3 inhibitors.…”

Section: Hsd17b3mentioning

confidence: 99%

Androgen-AR axis in primary and metastatic prostate cancer: chasing steroidogenic enzymes for therapeutic intervention

Pippione¹,

Boschi²,

Pors³

et al. 2017

JCMT

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Androgens play an important role in prostate cancer (PCa) development and progression. Although androgen deprivation therapy remains the front-line treatment for advanced prostate cancer, patients eventually relapse with the lethal form of the disease. The prostate tumor microenvironment is characterised by elevated tissue androgens that are capable of activating the androgen receptor (AR). Inhibiting the steroidogenic enzymes that play vital roles in the biosynthesis of testosterone (T) and dihydrotestosterone (DHT) seems to be an attractive strategy for PCa therapies. Emerging data suggest a role for the enzymes mediating pre-receptor control of T and DHT biosynthesis by alternative pathways in controlling intratumoral androgen levels, and thereby influencing PCa progression. This supports the idea for the development of multi-targeting strategies, involving both dual and multiple inhibitors of androgen-metabolising enzymes that are able to affect androgen synthesis and signalling at different points in the biosynthesis. In this review, we will focus on CYP17A1, AKR1C3, HSD17B3 and SRD5A, as these enzymes play essential roles in all the three androgenic pathways. We will review also the AR as an additional target for the design of bifunctional drugs. Targeting intracrine androgens and AKR1C3 have potential to overcome enzalutamide and abiraterone resistance and improve survival of advanced prostate cancer patients.

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“…Their purity (>95%) was confirmed by high performance liquid chromatography analysis. A compound previously identified by Bristol Myers Squibb (BMS) as a potential 17-HSD3 inhibitor (DBT 1; Fink et al, 2006), was synthesised using a modified published method (Yale et al, 1972). FBS, 2 mM L-glutamine, 0.075% sodium bicarbonate, and 250 µg/ml G418 (Sigma Aldrich Company Ltd.).…”

Section: Candidate 17-hsd3 Inhibitor Compoundsmentioning

confidence: 99%

Development of hormone-dependent prostate cancer models for the evaluation of inhibitors of 17β-hydroxysteroid dehydrogenase Type 3

Day¹,

Tutill²,

Foster³

et al. 2009

Molecular and Cellular Endocrinology

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This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Page 1 of 38A c c e p t e d M a n u s c r i p t

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Identification of a novel series of tetrahydrodibenzazocines as inhibitors of 17β-hydroxysteroid dehydrogenase type 3

Cited by 40 publications

References 17 publications

The design of novel 17β-hydroxysteroid dehydrogenase type 3 inhibitors

The design of novel 17β-hydroxysteroid dehydrogenase type 3 inhibitors

Androgen-AR axis in primary and metastatic prostate cancer: chasing steroidogenic enzymes for therapeutic intervention

Development of hormone-dependent prostate cancer models for the evaluation of inhibitors of 17β-hydroxysteroid dehydrogenase Type 3

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