Inhibition of the biosynthesis of proinflammatory cytokines such as tumor necrosis factor and interleukin-1 via p38 has been an approach toward the development of a disease modifying agent for the treatment of chronic inflammation and autoimmune diseases. The development of a new core structure of p38 inhibitors, 3-(4-fluorophenyl)-2-(pyridin-4-yl)-1H-pyrrolo[3,2-b] pyridine, is described. X-ray crystallographic data of the lead bound to the active site of p38 was used to guide the optimization of the series. Specific focus was placed on modulating the physical properties of the core while maintaining potent inhibition of p38. These efforts identified 42c as a potent inhibitor of p38, which also possessed the required physical properties worthy of advanced studies.
A simple, versatile, and general approach to the solution phase,
parallel synthesis of chemical libraries
conducted on a generalized or universal template, which allows the
preparation of multi-milligram quantities of each
individual member, is described. In each step of the sequence, the
reactants, unreacted starting material, reagents
and their byproducts are removed by simple liquid/liquid or
liquid/solid extractions providing the desired
intermediates
and final compounds in high purities (95% average) irrespective of the
reaction yields and without deliberate reaction
optimization.
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