2‑Aminopyridine-Based Mitogen-Activated Protein Kinase Kinase Kinase Kinase 4 (MAP4K4) Inhibitors: Assessment of Mechanism-Based Safety

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.