Journal of Medicinal Chemistry p. 3114 - 3125 (2018)
Update date:2022-08-05
Topics: Evaluation Inhibitors Safety Activity Binding Assessment Protein kinase 2-Aminopyridine Mechanism-based
Dow, Robert L.
Ammirati, Mark
Bagley, Scott W.
Bhattacharya, Samit K.
Buckbinder, Leonard
Cortes, Christian
El-Kattan, Ayman F.
Ford, Kristen
Freeman, Gary B.
Guimar?es, Cristiano R. W.
Liu, Shenping
Niosi, Mark
Skoura, Athanasia
Tess, David
Studies have linked the serine-threonine kinase MAP4K4 to the regulation of a number of biological processes and/or diseases, including diabetes, cancer, inflammation, and angiogenesis. With a majority of the members of our lead series (e.g., 1) suffering from time-dependent inhibition (TDI) of CYP3A4, we sought design avenues that would eliminate this risk. One such approach arose from the observation that carboxylic acid-based intermediates employed in our discovery efforts retained high MAP4K4 inhibitory potency and were devoid of the TDI risk. The medicinal chemistry effort that led to the discovery of this central nervous system-impaired inhibitor together with its preclinical safety profile is described.
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