Formula I Compounds Inhibit c-fms Kinase Selectivity
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Solution Overview
Problem
There is a need for selective and potent protein tyrosine kinase inhibitors, particularly for c-fms kinase, as overexpression or inappropriate expression of protein kinases is linked to various diseases including cancer and diabetes, and existing inhibitors may not be sufficiently effective.
Innovation Solution
Development of novel compounds of Formula I, which include specific structural elements such as various substituents and functional groups, to act as potent inhibitors of c-fms kinase, potentially inhibiting FLT3 tyrosine kinase activity as well, and can be used in combination with other kinase inhibitors.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing protein tyrosine kinase inhibitors are used, then some kinase activity is inhibited, but the inhibitors are not sufficiently effective and lack selectivity
Solution Approach 1:
The patent applies local quality by designing inhibitors with specific structural features (Formula I compounds with defined substituents R1-R7) that are tailored to interact with specific kinase sites. The compounds incorporate particular functional groups and stereochemical configurations (syn/anti relationships at R2 and R4) that provide selective binding to c-fms kinase and FLT3, thereby achieving both effectiveness and selectivity simultaneously
2Reliability
If potent kinase inhibitors are developed, then therapeutic efficacy is improved, but the complexity of the compound structure increases
Solution Approach 1:
The patent segments the inhibitor structure into distinct functional components as defined in Formula I: a core scaffold with specific substituents (R1-R7) that can be independently optimized. This segmentation allows the compound to achieve potent kinase inhibition through specific structural elements while maintaining manageable complexity through systematic variation of substituents rather than entirely new molecular architectures
Data Source
AI summary
The invention is directed to compounds of Formula I: wherein Z, X, J, R2 and W are set forth in the specification, as well as solvates, hydrates, tautomers and pharmaceutically acceptable salts thereof, that inhibit protein tyrosine kinases, especially c-fms kinase. Methods of treating autoimmune diseases; and diseases with an inflammatory component; treating metastasis from ovarian cancer, uterine cancer, breast cancer, prostate cancer, lung cancer, colon cancer, stomach cancer, hairy cell leukemia; and treating pain, including skeletal pain caused by tumor metastasis or osteoarthritis, or visceral, inflammatory, and neurogenic pain; as well as osteoporosis, Paget's disease, and other diseases in which bone resorption mediates morbidity including rheumatoid arthritis, and other forms of inflammatory arthritis, osteoarthritis, prosthesis failure, osteolytic sarcoma, myeloma, and tumor metastasis to bone with the compounds of Formula I, are also provided.