title: Synthesis and structure-activity relationship studies of novel dihydropyridones as androgen receptor modulators.
abstract: A library of 3-hydroxy-2,3-dihydropyridones was synthesized, and their activities as antiandrogens were tested in the human prostate cancer cell line LNCaP. Structure-activity relationship (SAR) studies resulted in the identification of a potent compound whose activity is comparable to that of MDV3100. Homology modeling and molecular mechanics were used to build a structural model of the androgen receptor-ligand binding domain and to investigate the structural basis of the antagonism. The model is qualitatively consistent with the observed SAR. Moreover, the enrichment plot shows that screening with the model performs significantly better than random screening. Therefore, the model probably represents a realistic conformation of the antagonist form and can be utilized for structure-based design of novel antiandrogens.
authors.affiliation: Laboratory of Synthetic Chemistry, Frederick National Laboratory for Cancer Research, SAIC Frederick, Inc. , Frederick, Maryland 21702, United States.
authors.forename: Antonella
authors.initials: A
authors.lastname: Pepe
authors.forename: Michael
authors.initials: M
authors.lastname: Pamment
authors.forename: Yeong Sang
authors.initials: YS
authors.lastname: Kim
authors.forename: Sunmin
authors.initials: S
authors.lastname: Lee
authors.forename: Min-Jung
authors.initials: MJ
authors.lastname: Lee
authors.forename: Kristin
authors.initials: K
authors.lastname: Beebe
authors.forename: Anton
authors.initials: A
authors.lastname: Filikov
authors.forename: Len
authors.initials: L
authors.lastname: Neckers
authors.forename: Jane B
authors.initials: JB
authors.lastname: Trepel
authors.forename: Sanjay V
authors.initials: SV
authors.lastname: Malhotra
mesh_terms: D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D011728:Pyridones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D011944:Receptors, Androgen / Q000737:chemistry / Q000378:metabolism*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D011728:Pyridones; D011944:Receptors, Androgen
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