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  • The requisite extended benzyl alcohols and and


    The requisite extended benzyl alcohols –, , and and final potential DFG-out binding hybrid inhibitors – and – were prepared as shown in , . Benzaldehyde was alkylated with -methoxybenzyl chloride and then reduced with sodium borohydride to give benzyl alcohol . Pyridine derivative was prepared by O-methylation of pyridone with trimethylsilyldiazomethane. Benzyl alcohols – were then reacted with dibromoaminopyrazine , followed by Suzuki coupling. Pyridine derivatives and were prepared starting with 5-bromo-2-chloro-3-methoxypyridine () as shown in . Displacement of the chloride with 4-methoxybenzyl alcohol followed by lithium–halogen exchange and trapping with DMF gives aldehyde . Aldehyde was reduced with sodium borohydride to give alcohol . Alcohol was reacted with followed by Suzuki coupling to give pyridine analog . Baeyer–Villiger rearrangement of aldehyde , followed by hydrolysis in methanolic sodium methoxide gave phenol . Nucleophilic displacement in the presence of cesium carbonate followed by Suzuki coupling gave analog . shows potency of compounds – and –. Incorporation of the -like DFG-out tail () resulted in a dramatic 36-fold enhancement in CSF-1R potency over , presumably properly accessing the deep binding pocket revealed in a DFG-out binding mode. Similarly, pyridine variants of this methoxyphenyl-PMB tail were also quite potent ( and ). In contrast to , these analogs have an additional oxygen dopaminergic in the linker between the hinge binding aminopyrazine and the DFG-out tail group, yet still inhibit CSF-1R with a high degree of potency. Pyridine analog demonstrates that the OCH linker can be shortened to a single oxygen atom, analogous to the 1-atom linker length of the scaffold, resulting in a slight improvement in CSF-1R potency. To ascertain whether compounds – and – were indeed binding in a DFG-out mode, compound was co-crystallized with CSF-1R. A relatively low resolution structure of with CSF-1R showed that was indeed binding in a DFG-out mode (). Although hydrogen bonding interactions cannot be definitively determined given the resolution of the crystallographic data, the methoxy and benzyloxy oxygen atoms are near D796 in a manner similar to . A hydrogen bonding interaction with this residue is likely a key requirement for binding and accessing the DFG-out deep pocket. By transforming a series of DFG-in CSF-1R inhibitors to DFG-out inhibitors, we have established a potent series more suitable for lead development. In contrast to –, which were less attractive in terms of MW, LE, LipE, and hERG potential, – and – have significantly reduced MW, Log, improved LipE, and reduced hERG potential (, ). For example, LipE’s were improved 2–3.5 orders of magnitude and MW’s were reduced into the 425–450 range. Furthermore, the potency and ligand/lipophilic efficiency enhancements were made in a more relevant cell-based assay system as opposed to a biochemical enzyme assay.
    In recent years, the growing understanding of the underlying role of protein tyrosine kinases in the abnormal signal transduction in cancer has sustained the development of numerous targeted small molecule tyrosine kinase inhibitors (TKIs) for cancer treatment., , TKIs stand as one of the fastest growing anticancer drug classes with 16 FDA-approved inhibitors within the last twelve years and hundreds more currently in development. Despite those clinical successes, the low response rates of those TKIs reaching the market forces the development of efficient tools to facilitate drug development and ultimately identify patients which are most likely to respond to treatment. The current use of invasive approaches such as tumor biopsy only provide partial information on specific target expression/mutation status. In this context, the advent of radiolabeled TKIs for positron emission tomography (PET) may potentially offer fundamental insights useful for drug development and individualized medicine as far as target expression, binding kinetics, potential toxicity and treatment efficacy is concerned., , , ,