Rational Design and Optimization of a Novel Class of Macrocyclic Apoptosis Signal-Regulating Kinase 1 Inhibitors

Le résumé fourni par la source

Structural analysis of a known apoptosis signal-regulating kinase 1 (ASK1) inhibitor bound to its kinase domain led to the design and synthesis of the novel macrocyclic inhibitor 8 (cell IC 50 = 1.2 μM). The profile of this compound was optimized for CNS penetration following two independent strategies: a rational design approach leading to 19 and a parallel synthesis approach leading to 26 . Both analogs are potent ASK1 inhibitors in biochemical and cellular assays ( 19, cell IC 50 = 95 nM; 26, cell IC 50 = 123 nM) and have moderate to low efflux ratio (ER) in an MDR1-MDCK assay ( 19, ER = 5.2; 26, ER = 1.5). In vivo PK studies revealed that inhibitor 19 had moderate CNS penetration ( K puu = 0.17) and analog 26 had high CNS penetration ( K puu = 1.0).

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