Calcitriol Derivatives with Heterocyclic Units in the Side-Chain

Calcitriol Derivatives with Heterocyclic Units in the Side-Chain 

Structural modifications of the calcitriol side-chain lead to changes in the biological activity profile of the respective compound series [191]. Introduction of the 22,23-double bond, transposition of the 25-OH group to the 24-position and connection of the terminal methyl groups of the side-chain afforded the so far clinically most relevant calcitriol analog, MC 903, from the Danish pharma manufacturer Leo Pharmaceutical Products [192].MC903has been successfully applied for the topical treatment of psoriasis [193] for a rather long time. 

After bromo-lithium exchange at low temperature the heterocyclic moieties were coupled with the aldehyde 3 giving access to the corresponding bissilyl protected 

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 relative binding affinities for the VDR were slightly reduced as compared to the natural hormone calcitriol. Thus, the side-chain modifications interfere only marginally with VDR binding (Table 10.5) [8], 

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