Synthesis of Potential Inhibitors of Vitamin D Hydroxylases

Before exerting its physiological action, vitamin D3 (1a, Fig. 1) must be hydroxylated in the liver to 25-hydroxyvitamin D3 (1b) by the enzyme 25-hydroxylase (25-OH-ase), and then in the kidney to 1α,25-dihydroxyvitamin D3 (1c) by 1α-OH-ase. This latter metabolite, whose mechanism of action is like that of steroid hormones, stimulates important physiological functions such as intestinal calcium absorption (ICA) and bone calcium mobilization (BOM).1 Interestingly, recent studies indicate that the hormone 1c is also involved in regulating cell proliferation and differentiation.2 Since we are interested in both the mode of action and biosynthetic pathways of 1c, and since research in the latter will be facilitated by inhibitors of vitamin D hydroxylases,3 we have started work on the design of inhibitors of the 25-OH-ase. Such compounds may also prove useful for treatment of diseases related with anomalous regulation of the enzyme.