SAR Based Design of Nicotinamides as a Novel Class of Androgen Receptor Antagonists for Prostate Cancer

Yang, Suhui; Song, Chunli; Van, Hue Thi My; Park, Eunsook; Khadka, Daulat Bikram; Gong, Eun-Yeung; Lee, Keesook; Cho, Won‐Jea

doi:10.1021/jm3014103

Cited by 24 publications

(15 citation statements)

References 26 publications

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“…Molecular modeling indicated that 4 adopts a “Y”-shape conformation and forms multiple hydrogen bonds with AR backbone in HBP (Zhou et al, 2009 ). Besides, via the SAR studies of the lead compound DIMN, Yang et al have synthesized a series of nicotinamides with extended linear scaffold bearing sterically bulky alkoxy groups on isoquinoline end and identified compounds 5 and 6 (Figure 4 ) as promising candidates of second generation antiandrogen for advanced PCa (Yang et al, 2013 ).…”

Section: Rational Antiandrogen Design To Circumvent Drug Resistance Dmentioning

confidence: 99%

Progress in antiandrogen design targeting hormone binding pocket to circumvent mutation based resistance

Tian

Zhou

2015

Front. Pharmacol.

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Androgen receptor (AR) plays a critical role in the development and progression of prostate cancer (PCa). Current clinically used antiandrogens such as flutamide, bicalutamide, and newly approved enzalutamide mainly target the hormone binding pocket (HBP) of AR. However, over time, drug resistance invariably develops and switches these antiandrogens from antagonist to agonist of the AR. Accumulated evidence indicates that AR mutation is an important cause for the drug resistance. This review will give an overview of the mutation based resistance of the current clinically used antiandrogens and the rational drug design to overcome the resistance, provides a promising strategy for the development of the new generation of antiandrogens targeting HBP.

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Section: Rational Antiandrogen Design To Circumvent Drug Resistance Dmentioning

confidence: 99%

Progress in antiandrogen design targeting hormone binding pocket to circumvent mutation based resistance

Tian

Zhou

2015

Front. Pharmacol.

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“…Recently, new derivatives [131] of DIMN (60), a potent and well characterised AR antagonist interacting with the LBD were designed and synthesised [132] . Some of these derivatives exhibited higher AR antagonistic activity than DIMN itself and bicalutamide, even with DHT co-treatment, and higher inhibitory effects on LNCaP cells proliferation.…”

Section: Seviteronel (5mentioning

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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“…non anilide-type molecules) is also a promising approach to overcome CRPC, and some AR antagonists bearing a unique skeleton or pharmacophore have been reported. 15,16 These compounds have a basic amino or phenolic hydroxyl group on the aromatic ring as the necessary polar group, instead of the cyano-or nitrophenyl group of the anilide-type antagonists.…”

Section: Figurementioning

confidence: 99%

Design and synthesis of 4-benzyl-1-(2H)-phthalazinone derivatives as novel androgen receptor antagonists

Inoue

Urushibara

Kanai

et al. 2015

European Journal of Medicinal Chemistry

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SAR Based Design of Nicotinamides as a Novel Class of Androgen Receptor Antagonists for Prostate Cancer

Cited by 24 publications

References 26 publications

Progress in antiandrogen design targeting hormone binding pocket to circumvent mutation based resistance

Progress in antiandrogen design targeting hormone binding pocket to circumvent mutation based resistance

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

Design and synthesis of 4-benzyl-1-(2H)-phthalazinone derivatives as novel androgen receptor antagonists

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