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

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

J Med Chem. 2018 Mar 23;:

Authors: Dow RL, Ammirati M, Bagley SW, Bhattacharya SK, Buckbinder L, Cortes C, El-Kattan AF, Ford K, Freeman GB, Guimaraes CRW, Liu S, Niosi M, Skoura A, Tess D

Abstract
Studies have linked the serine-threonine kinase MAP4K4 to the regulation of a number of biological processes/diseases including diabetes, cancer, inflammation and angiogenesis. With a majority of the members of our lead series (e.g. 1) suffer-ing from time-dependent inhibition 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 potent MAP4K4 inhibitory potency and were devoid of the TDI risk. The medicinal chemistry effort that led to the discovery of this CNS-impaired inhibitor together with its preclinical safety profile is described.

PMID: 29570292 [PubMed - as supplied by publisher]

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