Structure–activity relationships of 19-norvitamin D analogs having a fluoroethylidene group at the C-2 position

We have synthesized four new geometric isomers of 1α,25-dihydroxy-2-(2′-fluoroethylidene)-19-norvitamin D analogs 1 and 2 having a 20R- and 20S-configuration, whose structures are correlated with 2MD possessing high potencies in stimulating bone formation in vitro and in vivo. The E-isomers of (20R)- and (20S)-2-fluoroethylidene analogs 1a and 1b were comparable with the natural hormone 1α,25-(OH)2D3 in binding to the vitamin D receptor (VDR), while two Z-isomers 2a and 2b were about 15–20 times less active than the hormone. In inducing expression of the vitamin D responsive element-based luciferase reporter gene, the E-isomers 1a and 1b were 1.2- and 8.6-fold more potent than the hormone, respectively, while the Z-isomers 2a and 2b had 27–55% of the potency. On the basis of the biological activities and a docking simulation based on X-ray crystallographic analysis of the VDR ligand-binding pocket, the structure–activity relationships of the fluorinated 19-norvitamin D analogs are discussed.

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