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.
Synthesis and Biological Evaluation of Cyclopropylamine Vitamin D‐Like CYP24A1 Inhibitors / Chiellini, G.; Rapposelli, S.; Nesi, G.; Sestito, S.; Sabatini, M.; Zhu, J.; Massarelli, I.; Plum, L. A.; Clagett‐dame, M.; Deluca, H. F.. - In: CHEMISTRYSELECT. - ISSN 2365-6549. - 2:27(2017), pp. 8346-8353. [10.1002/slct.201701835]
Synthesis and Biological Evaluation of Cyclopropylamine Vitamin D‐Like CYP24A1 Inhibitors
Sestito, S.;
2017-01-01
Abstract
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.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
