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Synthesis and Biological Evaluation of Cyclopropylamine Vitamin D‐Like CYP24A1 Inhibitors
Author(s) -
Chiellini Grazia,
Rapposelli Simona,
Nesi Giulia,
Sestito Simona,
Sabatini Martina,
Zhu Jinge,
Massarelli Ilaria,
Plum Lori A.,
ClagettDame Margaret,
DeLuca Hector F.
Publication year - 2017
Publication title -
chemistryselect
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.437
H-Index - 34
ISSN - 2365-6549
DOI - 10.1002/slct.201701835
Subject(s) - calcitriol receptor , cyp24a1 , vitamin d and neurology , chemistry , biochemistry , receptor , biology , endocrinology
CYP24A1 hydroxylase plays a key role in tuning the levels and function of 1,25(OH) 2 D 3 , 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) 2 D 3 in binding for the vitamin D receptor (VDR) and transcriptional activity, while showing low calcemic activity in vivo.