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

Molecular knowledge of pure antagonism and systematic SAR study offered a direction for structural optimization of DIMN to provide nicotinamides as a novel series of AR antagonists. Nicotinamides with extended linear scaffold bearing sterically bulky alkoxy groups on isoquinoline end were synthesize...

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Bibliographic Details
Published inJournal of medicinal chemistry Vol. 56; no. 8; pp. 3414 - 3418
Main Authors Yang, Su Hui, Song, Chin-Hee, Van, Hue Thi My, Park, Eunsook, Khadka, Daulat Bikram, Gong, Eun-Yeung, Lee, Keesook, Cho, Won-Jea
Format Journal Article
LanguageEnglish
Published WASHINGTON American Chemical Society 25.04.2013
Amer Chemical Soc
Subjects
Androgen Antagonists - pharmacology
Androgen Receptor Antagonists - pharmacology
Androgen Receptor Antagonists - therapeutic use
Cell Line, Tumor
Chemistry, Medicinal
Drug Design
Humans
Isoquinolines - chemical synthesis
Isoquinolines - pharmacology
Life Sciences & Biomedicine
Male
Niacinamide - analogs & derivatives
Niacinamide - pharmacology
Pharmacology & Pharmacy
Prostatic Neoplasms - drug therapy
Receptors, Androgen - drug effects
Science & Technology
Structure-Activity Relationship
AMPLIFICATION
GENE
MECHANISM
STRUCTURAL BASIS
BEARING
LIGAND-BINDING DOMAIN
MUTATIONS
WITHDRAWAL SYNDROME
BICALUTAMIDE
PROGRESSION
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Summary:Molecular knowledge of pure antagonism and systematic SAR study offered a direction for structural optimization of DIMN to provide nicotinamides as a novel series of AR antagonists. Nicotinamides with extended linear scaffold bearing sterically bulky alkoxy groups on isoquinoline end were synthesized for H12 displacement. AR binding affinity and molecular basis of antiandrogenic effect establish the optimized derivatives, 7au and 7bb, as promising candidates of second generation AR antagonists for advanced prostate cancer.
Bibliography:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
ISSN:0022-2623
1520-4804
DOI:10.1021/jm3014103