Compounds and compositions for ossification and methods related thereto
Inventors
Boden, Scott D. • Sangadala, Sreedhara
Assignees
Emory University • US Department of Veterans Affairs
Publication Number
US-9808464-B2
Publication Date
2017-11-07
Expiration Date
2031-08-18
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Abstract
The disclosure relates to compounds and compositions for forming bone and methods related thereto. In one embodiment, the disclosure relates to a composition comprising a compound disclosed herein, such as 2,4-diamino-1,3,5-triazine derivatives or salts thereof, for use in bone growth processes. In a typical embodiment, a bone graft composition is implanted in a subject at a site of desired bone growth or enhancement.
Core Innovation
The invention relates to compounds and compositions for forming bone and methods related thereto. Specifically, it involves compositions comprising 2,4-diamino-1,3,5-triazine derivatives or salts thereof that modulate the interaction between Smurf1 and its natural target proteins in cells. These compounds can be included in bone graft compositions implanted at sites of desired bone growth or enhancement in a subject.
The problem addressed is the complications and limitations associated with traditional bone grafting, particularly when harvesting autologous grafts from the iliac crest. Such complications include pain, nerve damage, hematoma, wound complications, and cosmetic deformity. Additionally, existing synthetic bone grafts containing bone morphogenetic proteins (BMPs) like recombinant human BMP-2 face barriers due to high costs and the requirement for high concentrations to be effective. Therefore, there is a need for compositions that can substitute or complement BMPs in bone growth applications.
The invention identifies specific 2,4-diamino-1,3,5-triazine derivatives, such as 2,4-diamino-6-vinyl-1,3,5-triazine (Compound 12) and 1-(4-chlorophenyl)-4,6-diamino-1,2-dihydro-2,2-dimethyl-1,3,5-triazine (Compound 12X), which potentiate BMP-induced osteoblastic differentiation and bone growth. The compounds exhibit dose-dependent enhancement of BMP signaling markers such as alkaline phosphatase and osteocalcin mRNA expression, as well as BMP-specific luciferase activity. The compositions may also include bone morphogenetic proteins, growth factors, bone salts such as calcium phosphates, and graft matrices like collagen sponges or hydrogels.
Claims Coverage
The patent includes three independent claims covering methods of forming bone or cartilage, performing spinal fusion, and treating bone fractures using specified 2,4-diamino-1,3,5-triazine derivatives or their salts.
Method of forming bone or cartilage using graft compositions with specific 2,4-diamino-1,3,5-triazine derivatives
Implanting a graft composition comprising a 2,4-diamino-1,3,5-triazine derivative or salt thereof having a specified chemical formula in a subject under conditions to form bone or cartilage. The composition may include a bone morphogenetic protein and is implanted in a bony void, which may be due to surgical removal. The method can include securing bone structure movement with a fixation system that is removed after bone formation.
Method of performing spinal fusion using bone graft compositions with specified 2,4-diamino-1,3,5-triazine derivatives
Implanting a bone graft composition containing a 2,4-diamino-1,3,5-triazine derivative or salt thereof configured to promote bone growth between two vertebrae of a subject, optionally including a bone morphogenetic protein.
Method of preventing or treating bone fractures using pharmaceutical compositions with specified 2,4-diamino-1,3,5-triazine derivatives
Administering a pharmaceutical composition comprising a 2,4-diamino-1,3,5-triazine derivative or pharmaceutically acceptable prodrug or salt thereof to a subject at risk for, exhibiting symptoms of, or diagnosed with a bone fracture. Administration can be localized by percutaneous injection.
The claims collectively cover methods of bone and cartilage formation, spinal fusion, and bone fracture treatment using grafts or pharmaceutical compositions comprising specific 2,4-diamino-1,3,5-triazine derivatives or their salts, optionally combined with bone morphogenetic proteins, and entail implantation or administration under controlled conditions.
Stated Advantages
The compounds potentiate BMP-induced osteoblastic differentiation and bone formation, enhancing BMP signaling activity effectively.
Certain derivatives exhibit reduced hepatotoxicity probability, improving safety profiles compared to initial compounds.
Compositions reduce or eliminate the need for harvesting bone from remote sites, thus avoiding associated complications such as pain and nerve damage.
Documented Applications
Use in bone graft compositions for bone growth or enhancement by implantation in subjects at sites of desired bone regeneration.
Methods of performing spinal fusion by implanting compositions to grow bone between vertebrae in patients diagnosed with degenerative disc disease or back pain symptoms.
Treatment or prevention of bone fractures through pharmaceutical compositions containing the compounds.
Treatment or prevention of bone degenerative diseases such as osteoporosis, osteitis deformans, bone metastasis, multiple myeloma, primary hyperparathyroidism, and osteogenesis imperfecta.
Cartilage regeneration in areas such as intervertebral discs and various joints including jaw, elbow, knee, ankle, wrist, and hip.
Use in conjunction with implants, prosthetic devices, or anchors by implanting compositions at bone contact sites to promote bone integration.
Interested in licensing this patent?