Oxazole calcitriols

The biological effects of these novel oxazole calcitriol derivatives have been assessed at Schering. Initially it turned out that the 24-0 H stereochemistry is crucial for biological activity. As the 24a-OH analogs were only very weakly active (data not shown), their respective 24(1-014 counterparts exerted substantial activity in all systems investigated. 

The immunomodulatory activity of calcitriol derivatives can be investigated in PBMCs, giving hints for the application of such compounds in the treatment of immune disorders. All oxazole calcitriols possessing the 24(3-OH situation showed strong agonistic potency in this cell system. Overall, the butyl compound 28b was detected as the most potent analog in this assay, almost reaching the potency level of calcitriol. 

The induction of differentiation of HL-60 cells is a prominent assay to evaluate agonistic calcitriol behavior with certain relevance for cancer treatment. In this setting the first calcitriol antagonist, ZK 159222, has been identified by Schering researchers [195], The methyl (25b), ethyl (26b) and pentyl (29b) oxazole analogs showed dramatically reduced agonistic potency in this assay. On the other hand, the... 

In the rat model of hypercalcemia all oxazole compounds were substantially less active than calcitriol, offering the chance to establish a therapeutic window in vivo. 

In the course of the Schering calcitriol program a variety of other heterocyclic derivatives were synthesized and investigated. Apart from the oxazole series, thiazole calcitriols were identified as interesting substructures as well. 

Overall, the profile of the heterocyclic calcitriols is dependent on the nature of the heterocyde, the position of substitution and the length of the side-chain. Analysis of theobtained data led to thecondusion that butyl oxazole 28b (ZK191784) displayed the most promising partial agonistic profile which could potentially lead to tissue-selective activity. This compound was therefore selected to be characterized more intensively in vitro and in vivo. 

---