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• W2610185685 abstract "A high-throughput screening (HTS) of the Genentech/Roche library identified a novel, uncharged scaffold as a KDM5A inhibitor. Lacking insight into the binding mode, initial attempts to improve inhibitor potency failed to improve potency, and synthesis of analogs was further hampered by the presence of a C–C bond between the pyrrolidine and pyridine. Replacing this with a C–N bond significantly simplified synthesis, yielding pyrazole analog 35, of which we obtained a co-crystal structure with KDM5A. Using structure-based design approach, we identified 50 with improved biochemical, cell potency and reduced MW and lower lipophilicity (Log D) compared with the original hit. Furthermore, 50 showed lower clearance than 9 in mice. In combination with its remarkably low plasma protein binding (PPB) in mice (40%), oral dosing of 50 at 5 mg/kg resulted in unbound Cmax ∼2-fold of its cell potency (PC9 H3K4Me3 0.96 μM), meeting our criteria for an in vivo tool compound from a new scaffold." @default.
• W2610185685 created "2017-05-12" @default.
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• W2610185685 date "2017-07-01" @default.
• W2610185685 modified "2023-10-16" @default.
• W2610185685 title "From a novel HTS hit to potent, selective, and orally bioavailable KDM5 inhibitors" @default.
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• W2610185685 doi "https://doi.org/10.1016/j.bmcl.2017.05.016" @default.
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