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

• Published in: Journal of medicinal chemistry Vol. 62; no. 23; pp. 10740 - 10756
• Main Authors: Himmelbauer, Martin K, Xin, Zhili, Jones, J. Howard, Enyedy, Istvan, King, Kristopher, Marcotte, Douglas J, Murugan, Paramasivam, Santoro, Joseph C, Hesson, Thomas, Spilker, Kerri, Johnson, Joshua L, Luzzio, Michael J, Gilfillan, Rab, de Turiso, Felix Gonzalez-Lopez
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 12-12-2019
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.9b01206

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 (K puu = 0.17) and analog 26 had high CNS penetration (K puu = 1.0).