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J Med Chem. 2016 Aug 25;59(16):7544-60. doi: 10.1021/acs.jmedchem.6b00598. Epub 2016 Aug 17.

Discovery of Imidazoquinolines as a Novel Class of Potent, Selective, and in Vivo Efficacious Cancer Osaka Thyroid (COT) Kinase Inhibitors.

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1
Global Discovery Chemistry, ‡Analytical Sciences, §Center for Proteomic Chemistry, ∥Preclinical Safety, and ⊥Autoimmunity Transplantation Inflammation, Novartis Institutes for BioMedical Research , CH-4002 Basel, Switzerland.

Abstract

Cancer Osaka thyroid (COT) kinase is an important regulator of pro-inflammatory cytokines in macrophages. Thus, pharmacologic inhibition of COT should be a valid approach to therapeutically intervene in the pathogenesis of macrophage-driven inflammatory diseases such as rheumatoid arthritis. We report the discovery and chemical optimization of a novel series of COT kinase inhibitors, with unprecedented nanomolar potency for the inhibition of TNFα. Pharmacological profiling in vivo revealed a high metabolism of these compounds in rats which was demonstrated to be predominantly attributed to aldehyde oxidase. Due to the very low activity of hepatic AO in the dog, the selected candidate 32 displayed significant blood exposure in dogs which resulted in a clear prevention of inflammation-driven lameness. Taken together, the described compounds both potently and selectively inhibit COT kinase in primary human cells and ameliorate inflammatory pathologies in vivo, supporting the notion that COT is an appropriate therapeutic target for inflammatory diseases.

PMID:
27502541
DOI:
10.1021/acs.jmedchem.6b00598
[Indexed for MEDLINE]

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