Recently, we found that 2α-[2-(tetrazol-2-yl)ethyl]-1α,25-dihydroxyvitamin D showed higher osteocalcin promoter transactivation activity in human osteosarcoma (HOS) cells and a greater therapeutic effect in ovariectomized (OVX) rats in vivo than those of active vitamin D, 1α,25(OH)D. We were interested in introducing a heterocyclic ring to the C2 position of the seco-steroidal structure via an alkyl linker, and four novel C2-(3-tetrazolylpropyl) substituted 1α,25-dihydroxy-19-norvitamin D analogs, 2α-[3-(tetrazol-1-yl)propyl]-, 2β-[3-(tetrazol-1-yl)propyl]-, 2α-[3-(tetrazol-2-yl)propyl]-, and 2β-[3-(tetrazol-2-yl)propyl]-19-nor-1α,25(OH)D were synthesized. Among them, 2α-[3-(tetrazol-1-yl)propyl]-19-nor-1α,25(OH)D showed weak binding affinity for human vitamin D receptor (hVDR) (2.6% of 1α,25(OH)D and ca. 15% of 19-nor-1α,25(OH)D) and weak VDR transactivation activity in HOS cells (EC 7.3nM, when 1α,25(OH)D0.23nM). Although the other three compounds could not act as VDR binders by evaluation of the competition assays, 2α-[3-(tetrazol-2-yl)propyl]-19-nor-1α,25(OH)D showed weak transactivation activity (EC 12.5nM). Metabolic stability of the 2α-substituted compounds 2α-[3-(tetrazol-1-yl)propyl]- and 2α-[3-(tetrazol-2-yl)propyl]-19-nor-1α,25(OH)D was higher than that of the 2β-substituted counterparts 2β-[3-(tetrazol-1-yl)propyl]- and 2β-[3-(tetrazol-2-yl)propyl]-19-nor-1α,25(OH)D against human CYP24A1. Introduction of a tetrazole ring to the C2-position of the 19-norvitamin D skeleton with the propyl linker led to weak VDR agonistic activity with stability against CYP24A1 metabolism.
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