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Bioorg Med Chem. 2003 Aug 15;11(17):3621-31.

Design and synthesis of potent vitamin D receptor antagonists with A-ring modifications: remarkable effects of 2alpha-methyl introduction on antagonistic activity.

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  • 1Faculty of Pharmaceutical Sciences, Teikyo University, 199-0195, Sagamiko, Kanagawa, Japan. akittaka@pharm.teikyo-u.ac.jp

Abstract

Novel A-ring analogues of the vitamin D receptor (VDR) antagonist (3a), ZK-159222, and its 24-epimer (3b) were convergently synthesized. Preparation of the CD-ring portions with the side chains of 3a,b, followed by palladium-catalyzed cross-coupling with the A-ring enyne precursors (15a,b), (3S,4S,5R)- and (3S,4S,5S)-bis[(tert-butyldimethylsilyl)oxy]-4-methyloct-1-en-7-yne, afforded the 2alpha-methyl-introduced analogues (4a,b) and their 3-epimers (5a,b). The biological profiles of the hybrid analogues were assessed in terms of affinity for VDR, and antagonistic activity to inhibit HL-60 cell differentiation induced by the natural hormone, 1alpha,25-dihydroxyvitamin D(3). The analogue 4a showed an approximately fivefold higher antagonistic activity compared with 3a. The 2alpha-methyl introduction into 3a increased the receptor affinity, thereby enhancing VDR antagonism. This approach to design potent antagonists based on hybridization of structural motifs in the A-ring and in the side chain may prove to be valuable.

PMID:
12901907
[PubMed - indexed for MEDLINE]
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