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

  • J Med Chem. 2018 Apr 12;61(7):3114-3125. doi: 10.1021/acs.jmedchem.8b00152.
Robert L Dow  1 ,  Mark Ammirati  2 ,  Scott W Bagley  2 ,  Samit K Bhattacharya  1 ,  Leonard Buckbinder  1 ,  Christian Cortes  1 ,  Ayman F El-Kattan  1 ,  Kristen Ford  2 ,  Gary B Freeman  1 ,  Cristiano R W Guimarães  1 ,  Shenping Liu  2 ,  Mark Niosi  2 ,  Athanasia Skoura  1 ,  David Tess  1
Affiliations
  • 1. Pfizer Worldwide Research & Development , Cambridge , Massachusetts 02139 , United States.
  • 2. Pfizer Worldwide Research & Development , Groton , Connecticut 06340 , United States.
PMID: 29570292 DOI: 10.1021/acs.jmedchem.8b00152
Abstract

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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