Anaplastic lymphoma kinase (ALK) is a promising new target for therapy of certain cancers such as anaplastic large-cell lymphoma (ALCL) and inflammatory myofibroblastic tumor (IMT). We have identified a series of novel pyridones as kinase inhibitors of ALK by application of a stepwise process involving in vitro screening of a novel targeted library followed by iterative template modification based on medicinal chemistry insights and computational ranking of virtual libraries. Using this process, we discovered ALK-selective inhibitors with improved potency and selectivity. Herein the details of the design process and synthesis of these novel pyridones, along with their enzymatic and cell-based activity, are discussed.
We
identified and explored the structure–activity-relationship
(SAR) of an adamantane carboxamide chemical series of Ebola virus
(EBOV) inhibitors. Selected analogs exhibited half-maximal inhibitory
concentrations (EC50 values) of ∼10–15 nM
in vesicular stomatitis virus (VSV) pseudotyped EBOV
(pEBOV) infectivity assays, low hundred nanomolar EC50 activity
against wild type EBOV, aqueous solubility >20 mg/mL, and attractive
metabolic stability in human and nonhuman liver microsomes. X-ray
cocrystallographic characterizations of a lead compound with the EBOV
glycoprotein (GP) established the EBOV GP as a target for direct compound
inhibitory activity and further provided relevant structural models
that may assist in identifying optimized therapeutic candidates.
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