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.2013 Nov 14;56(21):8280-97.
doi: 10.1021/jm301714s. Epub 2013 Oct 30.

Synthesis and structure-activity relationship studies of novel dihydropyridones as androgen receptor modulators

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Synthesis and structure-activity relationship studies of novel dihydropyridones as androgen receptor modulators

Antonella Pepe et al. J Med Chem..

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.

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Figures

Figure 1
Figure 1
androgen receptor signaling pathway.
Figure 2
Figure 2
Antiandrogen molecules approved by the FDA
Figure 3
Figure 3
Structures of compounds tested and inhibition of PSA and TMPRSS2 mRNA expression at 5 μM.
Figure 4
Figure 4
Structures of compounds tested and inhibition of PSA and TMPRSS2 mRNA expression at 5 μM.
Figure 5
Figure 5
Structures of compounds tested and inhibition of PSA and TMPRSS2 mRNA expression at 5 μM.
Figure 6
Figure 6
Topliss’ decision tree
Figure 7
Figure 7
Inhibition of PSA and TMPRSS2 mRNA expression by(±)-13h or MDV3100 in the presence of R1881 at 20 h.
Figure 8
Figure 8
Binding study of MDV3100 vs13h
Figure 9
Figure 9
Growth curve of MDV3100 vs13h
Figure 10
Figure 10. Androgen receptor model of antagonistic form (GR template), violet ribbon
The aligned X-ray structure of agonistic form (PDB code 2AMB) is shown in gray. H3 helix is colored blue, H6 green, H7 black, H11 cyan, H12 red. The RU-486 ligand from the template structure (PDB code 1NHZ) is shown in green. The docked conformation of(±)-13h is shown in colored stick representation.
Figure 11
Figure 11. Binding site of androgen receptor model of antagonistic form based on the X-ray structure of the glucocorticoid receptor
The wire representation is the pocket surface detected by ICM PocketFinder. Sub-pockets that are formed in the antagonistic structure are designated SP1–SP4. The RU-486 ligand from the template structure (1NHZ antagonist form of GR) is shown in green. The colored molecule is the docked conformation of (±)-13h.
Scheme 1
Scheme 1. Reagents and conditions
i) PhCO2Cl, THF; ii) R1MgX; iii) OsO4, NMO, acetone, H2O; iv) 2-trifluoromethyl-4-fluorobenzoyl chloride, TEA, DMAP, THF; v) MeONa, MeOH; vi)N-Methyl-N-phenylcarbamoyl chloride, TEA, DMAP, THF; vii) R2Cl, DMAP, THF; viii) TBSCl, imidazole, CH2Cl2; ix) HF/pyridine, CH3CN, pyridine; x) R3COCl, Et3N, CH2Cl2.
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