Highly active analogs of 1 alpha,25-dihydroxyvitamin D-3 that resist metabolism through C-24 oxidation and C-3 epimerization pathways

The secosteroid hormone 1 alpha ,25-dihydroxyvitamin D-3 [1 alpha ,25(OH)(2 )D-3] is metabolized in its target tissues through modifications of both th e side chain and the A-ring. The C-24 oxidation pathway, the main side chai n modification pathway is initiated by hydroxylation at C-24 of the side ch ain and leads to the formation of the end product, calcitroic acid. The C-2 3 and C-26 oxidation pathways, the minor side chain modification pathways a re initiated by hydroxylations at C-23 and C-26 of the side chain and lead to the formation of the end product, calcitriol lactone. The C-3 epimerizat ion pathway, the newly discovered A-ring modification pathway is initiated by epimerization of the hydroxyl group at C-3 of the A-ring to form 1 alpha ,25(OH)(2)-3-epi-D-3. A rational design for the synthesis of potent analog s of 1 alpha ,25(OH)(2)D-3 is developed based on the knowledge of the vario us metabolic pathways of 1 alpha ,25(OH)(2)D-3. Structural modifications ar ound the C-20 position, such as C-20 epimerization or introduction of the 1 6-double bond affect the configuration of the side chain. This results in t he arrest of the C-24 hydroxylation initiated cascade of side chain modific ations at the C-24 oxo stage, thus producing the stable C-24 oxo metabolite s which are as active as their parent analogs. To prevent C-23 and C-24 hyd roxylations, cis or trans double bonds, or a triple bond are incorporated i n between C-23 and C-24. To prevent C-26 hydroxylation, the hydrogens on th ese carbons are replaced with fluorines. Furthermore, testing the metabolic fate of the various analogs with modifications of the A-ring, it was found that the rate of C-3 epimerization of 5,6-trans or 19-nor analogs is decre ased to a significant extent. Assembly of all these protective structural m odifications in single molecules has then produced the most active vitamin D-3 analogs 1 alpha ,25(OH)(2)-16,23-E-diene-26,27-hexafluoro-19-nor-D-3 (R o 25-9022), 1 alpha ,25(OH)(2)-16,23-Z-diene-26,27-hexafluopo-19-nor-D-3 (R o 26-2198), and 1 alpha ,25(OH)(2)-16-ene-23-yne-26,27-hexafluoro-19-nor-D- 3 (Ro 25-6760), as indicated by their antiproliferative activities. (C) 200 1 Elsevier Science Inc. All rights reserved.