Synthesis, metabolism, and biological activity of 2-[3-(tetrazolyl)propyl]-1α,25-dihydroxy-19-norvitamin D3

Recently, we found that 2 alpha-[2-(tetrazol-2-yl)ethyl]-1 alpha,25-dihydroxyvitamin D-3 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-3, 1 alpha,25(OH)(2)D-3. 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 1 alpha,25-dihydroxy-19-norvitamin D-3 analogs, 2 alpha-[3-(tetrazol-1-yl)propyl]-, 2 beta-[3-(tetrazol-1-yl)propyl]-, 2 alpha-[3-(tetrazol-2-yepropyl]-, and 2 beta-[3-(tetrazol-2-yl)propyl]-19-nor-1 alpha,25(OH)(2)D-3 were synthesized. Among them, 2 alpha-[3-(tetrazol-1-yl)propyl]-19-nor-1 alpha,25(OH)(2)D-3 showed weak binding affinity for human vitamin D receptor (hVDR) (2.6% of 1 alpha,25(OH)(2)D-3 and ca. 15% of 19-nor-1 alpha,25(OH)(2)D-3) and weak VDR transactivation activity in HOS cells (EC50 7.3 nM, when 1 alpha,25(OH)(2)D-3 0.23 nM). Although the other three compounds could not act as VDR binders by evaluation of the competition assays, 2 alpha-[3-(tetrazol-2-yl)propyl]-19-nor-1 alpha,25(OH)(2)D-3 showed weak transactivation activity (EC50 12.5 nM). Metabolic stability of the 2 alpha-substituted compounds 2 alpha-[3-(tetrazol-1-yl)propyl]- and 2 alpha-[3-(tetrazol-2-yl)propyl]-19-nor-1 alpha,25(OH)(2)D-3 was higher than that of the 2 beta-substituted counterparts 2 alpha-[3-(tetrazol-1-yl)propyl]- and 2 beta-[3-(tetrazol-2yl)propyl]-19-nor-1 alpha,25(OH)(2)D-3 against human CYP24A1. Introduction of a tetrazole ring to the C2-position of the 19-norvitamin D-3 skeleton with the propyl linker led to weak VDR agonistic activity with stability against CYP24A1 metabolism. (C) 2015 Elsevier Ltd. All rights reserved.