jm9b01206_si_001.pdf (777.31 kB)
Rational Design and Optimization of a Novel Class of Macrocyclic Apoptosis Signal-Regulating Kinase 1 Inhibitors
journal contribution
posted 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 TurisoStructural 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).