title: Synthesis and biological activities of a new series of secosteroids: vitamin D phosphonate hybrids.
abstract: By a structural combination of phosphonate and bisphosphonate moieties with the vitamin D skeleton a series of new vitamin D analogs was synthesized. Derivatives with 24beta-hydroxy- or 24-keto groups exerted considerable vitamin D activities in vitro while the hypercalcemic potentials were significantly reduced as compared to 1alpha,25-dihydroxyvitamin D(3) (calcitriol). Whereas the 24-hydroxy analogs did not influence bone formation in vivo in dosages below the hypercalcemic threshold, the 24-ketones were found to induce synthesis of new bone matrix in non-hypercalcemic doses. Vitamin D bisphosphonate hybrids, on the other hand, which did not elicit substantial vitamin D activities in vitro and tend to decrease serum calcium levels in vivo clearly induced osteoid formation in rats, indicating a mechanism of action different to calcitriol.
authors.affiliation: Preclinical Drug Research, Schering AG, Institute of Medicinal Chemistry, Muellerstrasse 178, D-13342, Berlin, Germany. andreas.steinmeyer@schering.de
authors.forename: A
authors.initials: A
authors.lastname: Steinmeyer
authors.forename: K
authors.initials: K
authors.lastname: Schwarz
authors.forename: M
authors.initials: M
authors.lastname: Haberey
authors.forename: G
authors.initials: G
authors.lastname: Langer
authors.forename: H
authors.initials: H
authors.lastname: Wiesinger
mesh_terms: D000818:Animals; D001857:Bone Matrix / Q000187:drug effects; D002117:Calcitriol / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects; D004164:Diphosphonates / Q000737:chemistry; D018922:HL-60 Cells; D006801:Humans; D006934:Hypercalcemia / Q000188:drug therapy; D063065:Organophosphonates / Q000737:chemistry; D015675:Osteocalcin / Q000096:biosynthesis / Q000187:drug effects; D011485:Protein Binding; D051381:Rats; D018167:Receptors, Calcitriol / Q000378:metabolism; D012632:Secosteroids / Q000138:chemical synthesis* / Q000494:pharmacology*; D013552:Swine; D014807:Vitamin D / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology
chemical_list: D004164:Diphosphonates; D063065:Organophosphonates; D018167:Receptors, Calcitriol; D012632:Secosteroids; D015675:Osteocalcin; D014807:Vitamin D; D002117:Calcitriol