Novel oxysterols activate the Hedgehog pathway and induce osteogenesis.
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.
Fate Therapeutics, 3535 General Atomics Court, Suite 200, San Diego, CA 92121, USA. franks@chem.ucla.edu
Frank
F
Stappenbeck
Wei
W
Xiao
Matt
M
Epperson
Mariko
M
Riley
Aaron
A
Priest
Danwen
D
Huang
KhanhLinh
K
Nguyen
Michael E
ME
Jung
R Scott
RS
Thies
Francine
F
Farouz
D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D008968:Molecular Conformation; D010006:Osteoblasts / Q000166:cytology / Q000187:drug effects; D010012:Osteogenesis / Q000187:drug effects*; D051381:Rats; D013123:Spinal Fusion; D013261:Sterols / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D013261:Sterols