ASK1, a member of the mitogen-activated protein kinase kinase kinase (MAPK3) family, is a key mediator in the apoptotic and inflammatory cellular stress response. Our studies, designed to probe the therapeutic value of modulating this pathway in preclinical models of neurological disease, focused on two strategies: Deconstruction of the solvent exposed region of known ASK1 Inhibitor Selonsertib (1) followed by macrocyclization of the resulting simplified pharmacophore to afford novel macrocyclic inhibitors (2). Optimization of the phenyl group of the same simplified structure with polar 5-membered heterocycles designed to place polar substituents in the solvent exposed area of the protein (3). Despite encouraging results, compound 2 suffered from a poor PK profile and compound 3 was not well tolerated upon chronic dosing. Further optimization of compound 3, to improve in vivo tolerability, resulted in the discovery of (4), a potent and selective ASK1 inhibitor with suitable PK and brain penetration for proof of pharmacology studies.

Design and optimization of potent, selective and brain penetrant apoptosis signal-regulating kinase 1 (ASK1) inhibitors

Fall 2022 abstracts, posters, and presentations will launch in mid-September.

ACS Fall 2022

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.