title: Methyl substitution of the 25-hydroxy group on 2-methylene-19-nor-1alpha,25-dihydroxyvitamin D3 (2MD) reduces potency but allows bone selectivity.
abstract: The discovery of 2-methylene-19-nor-1alpha,25-dihydroxyvitamin D3 (2MD) as a bone selective and bone anabolic form of vitamin D has stimulated an investigation of structure/function of bone selectivity. Four new 2-substituted-19-norvitamin D analogs 3-6 have been developed to study the structure-activity relationship at C-25. As predicted, removing the 25-hydroxy group (compound 3) from the very potent analog 2MD and its 2-methyl derivatives (5 and 6) dramatically reduces in vitro activities, but biological potency is nearly fully restored in vivo likely due to in vivo 25-hydroxylation. The introduction of a methyl group at C-25 (compound 4) that blocks in vivo 25-hydroxylation reduces biological activity both in vitro and in vivo. However, analog 4 retains bone selectivity making it interesting as a possible therapeutic for bone loss diseases.
authors.affiliation: Department of Biochemistry, University of Wisconsin-Madison, 433 Babcock Drive, Madison, WI 53706, USA. pawel@biochem.wisc.edu
authors.forename: Pawel
authors.initials: P
authors.lastname: Grzywacz
authors.forename: Lori A
authors.initials: LA
authors.lastname: Plum
authors.forename: Rafal R
authors.initials: RR
authors.lastname: Sicinski
authors.forename: Margaret
authors.initials: M
authors.lastname: Clagett-Dame
authors.forename: Hector F
authors.initials: HF
authors.lastname: DeLuca
mesh_terms: D000818:Animals; D001862:Bone Resorption / Q000188:drug therapy / Q000378:metabolism; D001842:Bone and Bones / Q000378:metabolism; D002117:Calcitriol / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004357:Drug Synergism; D005260:Female; D018922:HL-60 Cells; D006801:Humans; D051379:Mice; D009928:Organ Specificity; D013329:Structure-Activity Relationship; D014815:Vitamins / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D014815:Vitamins; D002117:Calcitriol