Molecular Pharmacology, Vol 20, 460-462, Copyright © 1981 by the American Society for Pharmacology and Experimental Therapeutics

Bone Resorptive Activity of Side-Chain Fluoro Derivatives of 25-Hydroxy- and 1,25-Dihydroxyvitamin D₃ in Culture

¹ Department of Pharmacology, Northwestern University, Chicago, Illinois 60611, Department of Biochemistry, College of Agricultural and Life Sciences, University of Wisconsin, Madison, Wisconsin 53706, Laboratory of Chemistry for Natural Products, Tokyo Institute for Natural Products, Tokyo Institute for Technology, and Tokyo College of Pharmacology, Tokyo, Japan

Three side-chain fluorinated analogues of vitamin D₃ were tested for their bone-resorbing activity on fetal rat forelimb bones in vitro. Two fluoro derivatives of 25-hydroxyvitamin D₃ (25-OH-D₃), 24,24-difluoro-25-hydroxyvitamin D₃ and 25-hydroxy-26,26,26,27,27,27-hexafluorovitamin D₃, were compared with 25-OH-D₃. The difluoro compound was approximately 7 times more potent than 25-OH-D₃, and the hexafluoro analogue was approximately 40 times more potent than 25-OH-D₃ in this system. In contrast, the 24,24-difluoro analogue of l,25-dihydroxyvitamin D₃ (l,25-(OH)₂D₃) was slightly less potent than l,25-(OH)₂D₃. The results indicate that the presence of fluoride groups on carbon atoms immediately adjacent to the 25-hydroxyl group enhances the in vitro bone-resorbing effects of 25-hydroxyvitamin D₃. On the other hand, fluorination of the l-hydroxylated compound on position 24 actually diminished rather than increased bone-resorptive activity.

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ACKNOWLEDGMENT We thank Thalia Mavreas for her excellent technical assistance.