%0 Journal Article %J Journal of Medicinal Chemistry %D 2002 %T 2-Ethyl and 2-ethylidene analogues of 1alpha,25-dihydroxy-19-norvitamin D(3): synthesis, conformational analysis, biological activities, and docking to the modeled rVDR ligand binding domain. %A Rafal R. Sicinski %A Piotr Rotkiewicz %A Andrzej KoliƄski %A Wanda Sicinska %A Jean M. Prahl %A Connie M. Smith %A Hector F. DeLuca %K Animals %K Binding Sites %K Biological Transport %K Calcitriol %K Calcium %K Cell Differentiation %K Chromatography, High Pressure Liquid %K HL-60 Cells %K Humans %K Intestinal Mucosa %K Ligands %K Magnetic Resonance Spectroscopy %K Male %K Models, Molecular %K Molecular Conformation %K Rats %K Receptors, Calcitriol %K Spectrophotometry, Ultraviolet %K Structure-Activity Relationship %K Swine %X Novel 19-nor analogues of 1alpha,25-dihydroxyvitamin D(3) were prepared and substituted at C-2 with an ethylidene group. The synthetic pathway was via Wittig-Horner coupling of the corresponding A-ring phosphine oxides with the protected 25-hydroxy Grundmann's ketones. Selective catalytic hydrogenation of 2-ethylidene analogues provided the 2alpha- and 2beta-ethyl compounds. The 2-ethylidene-19-nor compounds with a methyl group from the ethylidene moiety in a trans relationship to the C(6)-C(7) bond (E-isomers) were more potent than the corresponding Z-isomers and the natural hormone in binding to the vitamin D receptor. Both geometrical isomers (E and Z) of (20S)-2-ethylidene-19-norvitamin D(3) and both 2alpha-ethyl-19-norvitamins (in the 20R- and 20S-series) have much higher HL-60 differentiation activity than does 1alpha,25-(OH)(2)D(3). Both E-isomers (20R and 20S) of 2-ethylidene vitamins are characterized by very high calcemic activity in rats. The three-dimensional structure model of the rat vitamin D receptor and the computational docking of four synthesized (20R)-19-norvitamin D(3) analogues into its binding pocket are also reported. %B Journal of Medicinal Chemistry %V 45 %P 3366-80 %8 2002 Aug 1 %G eng %N 16