Novel oxysterols activate the Hedgehog pathway and induce osteogenesis

• Published in: Bioorganic & medicinal chemistry letters Vol. 22; no. 18; pp. 5893 - 5897
• Main Authors: Stappenbeck, Frank, Xiao, Wei, Epperson, Matt, Riley, Mariko, Priest, Aaron, Huang, Danwen, Nguyen, KhanhLinh, Jung, Michael E., Scott Thies, R., Farouz, Francine
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 15.09.2012; Elsevier
• Subjects: Animal models; Animals; Biological and medical sciences; Bone formation; Bone growth; Cell Differentiation - drug effects; Chemistry; Chemistry, Medicinal; Chemistry, Organic; Deuterium incorporation; Dose-Response Relationship, Drug; Fractures; Hedgehog signaling; Humans; Life Sciences & Biomedicine; Liver; Medical sciences; Microsomes; Microsomes, Liver - drug effects; Microsomes, Liver - metabolism; Molecular Conformation; Nonunion; Orthopedics; Osteoblastogenesis; Osteoblasts - cytology; Osteoblasts - drug effects; Osteogenesis; Osteogenesis - drug effects; Oxysterols; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Physical Sciences; Rats; Science & Technology; Spinal Fusion; Sterols - chemical synthesis; Sterols - chemistry; Sterols - pharmacology; Structure-Activity Relationship; Structure-activity relationships; Hedgehog signaling; Bone formation; Deuterium incorporation; Structure–activity relationship; Oxysterols; Spinal fusion; Structure-activity relationship; BONE; DIFFERENTIATION; Deuterium; Steroid; Incorporation; Hydrogen Isotopes; Cholesterol; Signal transduction; Structure activity relation; Hedgehog signaling pathway; Degradation product; Osteogenesis
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2012.07.073

Structure–activity relationship studies of oxysterol 4 have identified analogues such as 18, 21 and 30. These analogues are characterized by higher potency in a osteoblast differentiation assay and/or by increased metabolic stability in human liver microsomes. Oxysterols 4, 18 and 21 were evaluated in vivo in a rat spinal fusion model. Localized induction of bone formation is essential during orthopedic procedures that involve skeletal repair, such as surgical treatment of non-union bone fractures and degenerative disk disease. Herein we disclose the synthesis and biological evaluation of novel oxysterol derivatives designed as anabolic bone growth agents. Structure–activity relationship studies of oxysterol 4 have identified analogues such as 18, 21 and 30. These new analogues are characterized by higher potency in an osteoblast differentiation assay and/or by increased metabolic stability in human liver microsomes. Oxysterols 4, 18 and 21 were evaluated in vivo in a rat spinal fusion model.