jm9b01206_si_001.pdf (777.31 kB)
Rational Design and Optimization of a Novel Class of Macrocyclic Apoptosis Signal-Regulating Kinase 1 Inhibitors
journal contributionposted on 2019-11-26, 11:43 authored by Martin K. Himmelbauer, Zhili Xin, J. Howard Jones, Istvan Enyedy, Kristopher King, Douglas J. Marcotte, Paramasivam Murugan, Joseph C. Santoro, Thomas Hesson, Kerri Spilker, Joshua L. Johnson, Michael J. Luzzio, Rab Gilfillan, Felix Gonzalez-Lopez de Turiso
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 IC50 = 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 IC50 = 95 nM; 26, cell IC50 = 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 (Kpuu = 0.17) and analog 26 had high CNS penetration (Kpuu = 1.0).