ABSTRACT
A series of amidoheteroaryl compounds were designed and synthesized as inhibitors of B-Raf kinase. Several compounds from the series show excellent potency in biochemical, phenotypic and mode of action cellular assays. Potent examples from the series have also demonstrated good plasma exposure following an oral dose in rodents and activity against the Ras-Raf pathway in tumor bearing mice.
Subject(s)
Chemistry, Pharmaceutical/methods , Enzyme Inhibitors/chemical synthesis , Mutation , Proto-Oncogene Proteins B-raf/antagonists & inhibitors , Administration, Oral , Animals , Drug Design , Enzyme Inhibitors/pharmacology , Humans , Inhibitory Concentration 50 , Mice , Models, Chemical , Rats , Structure-Activity Relationship , raf Kinases/metabolism , ras Proteins/metabolismABSTRACT
The bisamide class of kinase inhibitors was identified as being active against CSF-1R. The synthesis and SAR of pyridyl and thiazolyl bisamides are reported, along with the pharmacokinetic properties and in vivo activity of selected examples.
Subject(s)
Amides/pharmacology , Antineoplastic Agents/pharmacology , Neoplasms/drug therapy , Neoplasms/metabolism , Receptor, Macrophage Colony-Stimulating Factor/antagonists & inhibitors , Thiazoles/pharmacology , 3T3 Cells , Amides/chemistry , Amides/pharmacokinetics , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacokinetics , Female , Humans , Mice , Mice, Nude , Rats , Receptor, Macrophage Colony-Stimulating Factor/genetics , Thiazoles/chemistry , Thiazoles/pharmacokineticsABSTRACT
Critical to the effective implementation of high throughput methods of synthesis is the necessity for a significant supporting level of automation. There are a number of critical issues associated with the successful introduction, and supporting role, of automation of small molecule chemical synthesis. Clearly there are needs for automation to increase drug candidate synthesis throughput. Automation of repetitive and laborious tasks associated with the synthesis process can release skilled chemists to apply their talents to the more challenging investigational aspects of developing new synthetic protocols. This provides continuity in the compound supply pipeline and ensures an optimal use of the automated platform for compound production. The very high fidelity of performing repetitive processes that can be managed through automation also removes some of the limitations and errors associated with more fallible human operators. This can include very difficult tasks associated with tracking data, and general information and inventory management. Taken collectively, these attributes associated with automation can lead to greater efficiencies, throughputs and improved allocation of human resources with concomitant reductions in costs associated with current day and future drug discovery. In our library development/synthesis paradigm, we feel that automation support must be invoked early in the process and that this automation support must continue throughout the project.
