Synthesis and Biological Evaluation of Cyclopropylamine Vitamin D‐Like CYP24A1 Inhibitors. Issue 27 (21st September 2017)

• Record Type: Journal Article
• Authors: Chiellini, Grazia; Rapposelli, Simona; Nesi, Giulia; Sestito, Simona; Sabatini, Martina; Zhu, Jinge; Massarelli, Ilaria; Plum, Lori A.; Clagett‐Dame, Margaret; DeLuca, Hector F.
• Is Part Of: ChemistrySelect. Volume 2:Issue 27(2017)
• Page Start: 8346
• Page End: 8353
• Publication Date: 2017-09-21
• Subjects: cancer therapy -- CYP24A1 hydroxylase -- cytochrome P450 inhibitors -- 1, 25-dihydroxyvitamin D3 -- molecular docking; Chemistry -- Periodicals; 540.5
• DOI: 10.1002/slct.201701835
• Languages: English
• ISSNs: 2365-6549

Abstract

Abstract: CYP24A1 hydroxylase plays a key role in tuning the levels and function of 1, 25(OH)2 D3, 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 D3 in binding for the vitamin D receptor (VDR) and transcriptional activity, while showing low calcemic activity in vivo. Abstract : Inhibition of CYP24A1 is expected to extend the half‐life of calcitriol. N‐25‐cyclo‐propylamine vitaminD‐like analog CPA1 was previously found to potently inhibit CYP24A1. To gain more insight into the SAR of CYP24 inhibitors, N‐23 (VN‐23) and N‐24 (24NP ) CPA1 analogs were prepared and tested. A N‐25‐sulfonamide analog of CPA1 (SAP‐3) was also evaluated. SAP‐3 and VN‐23 analogs were found to be potent inhibitors of CYP24A1.