Ligands with a 3,3-diphenylpentane skeleton for nuclear vitamin D and androgen receptors: Dual activities and metabolic activation

Ligands possessing dual vitamin D3 (VD3)-agonistic and androgen–antagonistic activities with various activity spectra were prepared based on a substituted 3,3-diphenylpentane (DPP) skeleton. Among the compounds, (R,S)-DPP-1023 [(R,S)-7b] and (S,S)-DPP-0123 [(S,S)-7c] showed the most potent vitamin D3-agonistic activity [with potency comparable to that of 1α,25-dihydroxyvitamin D3 (1,25-VD3)] and nuclear androgen receptor (AR)-binding activity (with higher affinity than that of hydroxyflutamide), respectively. Metabolic activation (reduction of the carbonyl group) of pivaloyl analogs [DPP-1113 (3a), DPP-1013 (3b), DPP-0113 (3c), and DPP-0013 (3d)] in HL-60 cells was found to be necessary for binding to nuclear vitamin D3 receptor (VDR).

Ligands possessing dual vitamin D3-agonistic and androgen–antagonistic activities with various activity spectra were prepared based on a substituted 3,3-diphenylpentane skeleton.Figure optionsDownload as PowerPoint slide