Metabolic Interactions of Side-chain Extended and Unsaturated Vitamin D Analogs with Cytochrome P450 Enzymes: Integrating Theoretical and Experimental Approaches.

ABSTRACT: The clinical use of 1,25-dihydroxycholecalciferol (1,25D3), the active form of vitamin D₃, is limited by its calcemic side effects and rapid metabolic degradation. To overcome these limitations, we designed novel vitamin D analogs with extended, rigidified, and branched side chains. Among them, PRI-1938, featuring a 5,6-trans triene system and 22,24-all-trans side-chain geometry, demonstrated markedly enhanced resistance to enzymatic catabolism. In vitro assays revealed that metabolic conversion of PRI-1938 by the nonselective cytochrome P450 3A4 (CYP3A4) enzyme was ca. 4-fold lower than that of the previously obtained PRI-1906 and over 9-fold lower than 1,25D3. All new analogs, including PRI-1927 and PRI-1937, exhibited significa

SUBMITTER: Zolek T 

PROVIDER: S-EPMC12467546 | biostudies-literature | 2025 Aug

REPOSITORIES: biostudies-literature