Synthesis and Biological Evaluation of Cyclopropylamine Vitamin D‐Like CYP24A1 Inhibitors

CYP24A1 hydroxylase plays a key role in tuning the levels and function of 1,25(OH)2D3, and inhibitors of CYP24 may be used for the treatment of a wide variety of clinical conditions. In the present work we describe the synthesis and biological properties of a small series of novel cyclopropylamine vitamin D-like CYP24A1 inhibitors, designed as structural analogues of our previously described cyclopropylamine vitamin D-like highly selective CYP24A1 inhibitor, CPA1. When tested in a cell-free assay, two of these compounds, namely VN-23 and SAP-3, were found to be potent inhibitors of CYP24A1, with compound VN-23 exhibiting selectivity with respect to CYP27B1 almost comparable to that of the lead compound CPA1. Interestingly, although compound SAP-3, is only moderately selective with respect to CYP27B1, it is almost as potent as 1,25(OH)2D3 in binding for the vitamin D receptor (VDR) and transcriptional activity, while showing low calcemic activity in vivo.