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-10888565-B2
Publication Date
2021-01-12
Expiration Date
2031-08-18
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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 promoting bone formation and ossification, specifically focusing on 2,4-diamino-1,3,5-triazine derivatives or salts thereof. The disclosed compositions can be used alone or in combination with bone morphogenetic proteins (BMPs) and other growth factors to enhance or induce bone growth processes. Typical embodiments involve implanting a bone graft composition comprising such compounds at a site where bone growth or enhancement is desired.
The problem addressed arises from the complications associated with harvesting autologous bone grafts, such as pain, nerve damage, and cosmetic deformities linked to donor sites like the iliac crest. Additionally, synthetic grafts containing BMPs face limitations due to high costs and the need for high BMP concentrations. Therefore, there is a need for compositions that can substitute or complement BMPs to treat bone-related conditions effectively and economically.
The invention provides compounds capable of modulating the interaction of Smurf1, an intracellular regulator that targets Smad1/5 proteins for degradation, thereby affecting BMP signaling. By modulating Smurf1 interactions with its natural targets, these compounds potentiate BMP-mediated osteoblastic differentiation and bone formation. The disclosure includes specific chemical entities, such as 2,4-diamino-6-vinyl-1,3,5-triazine and 1-(4-chlorophenyl)-4,6-diamino-1,2-dihydro-2,2-dimethyl-1,3,5-triazine, and details their chemical structures, derivatives, and salts, as well as methods of use and formulations for graft compositions.
Claims Coverage
The claims of the patent focus on methods for treating osteoporosis using specific 2,4-diamino-1,3,5-triazine derivatives and salts thereof. There are two independent claims addressing the administration of distinct compounds for such treatment.
Method of treating osteoporosis with 1-(4-chlorophenyl)-5-isopropyl-biguanide or salt thereof
This inventive feature covers administering an effective amount of 1-(4-chlorophenyl)-5-isopropyl-biguanide, or its salt, to a subject in need, notably a human diagnosed with osteoporosis.
Method of treating osteoporosis with 1-(4-chlorophenyl)-4,6-diamino-1,2-dihydro-2,2-dimethyl-1,3,5-triazine or salt thereof
This inventive feature involves administering an effective amount of 1-(4-chlorophenyl)-4,6-diamino-1,2-dihydro-2,2-dimethyl-1,3,5-triazine, or its salt, to a subject in need, especially a human subject diagnosed with osteoporosis.
The claims cover methods of treating osteoporosis through the administration of specified 2,4-diamino-1,3,5-triazine derivatives or salts, targeting human subjects diagnosed with the disease, thereby protecting specific therapeutic uses of these compounds.
Stated Advantages
Provides compounds that potentiate BMP-induced bone formation without the high cost and high dosage requirements associated with BMPs alone.
Reduces complications associated with autologous bone graft harvesting by providing alternative synthetic graft compositions.
Enhances BMP signaling by modulating Smurf1 interactions, promoting efficient osteoblastic differentiation and ossification.
Documented Applications
Use in bone graft compositions implanted at desired bone growth or enhancement sites.
Methods of forming bone or cartilage in subjects with bone voids caused by surgery, physical abnormalities, or injury.
Method of performing spinal fusion to immobilize vertebrae and relieve pain.
Therapeutic treatment of bone fractures and bone degenerative diseases, including osteoporosis, osteitis deformans, bone metastasis, multiple myeloma, primary hyperparathyroidism, and osteogenesis imperfecta.
Co-administration with bone morphogenetic proteins and other growth factors for bone repair and regeneration.
Use in bone tissue engineering combining compounds with osteogenic or pluripotent cells.
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