Glatthar, Ralf, Stojanovic, Aleksandar, Troxler, Thomas J., Mattes, Henri, Moebitz, Henrik, Beerli, Rene, Blanz, Joachim, Gassmann, Ernst, Drueckes, Peter, Fendrich, Gabriele, Gutmann, Sascha, Martiny-Baron, Georg, Spence, Fiona, Peel, John Edmondson and Sparrer, Helmut (2016) Discovery of imidazoquinolines as a novel class of potent, selective and in vivo efficacious COT kinase inhibitors. Journal of Medicinal Chemistry, 59 (16). pp. 7544-7560. ISSN 0022-2623

Abstract

COT kinase (TPl2, MAP3K8) is an important regulator of the pro-inflammatory cytokines TNFalpha and IL-1beta in macrophages. Thus, pharmacologic inhibition of Cot should be a valid approach to therapeutically intervene in the pathogenesis of rheumatoid arthritis and other macrophage-driven inflammatory diseases in humans. We here report the discovery and chemical optimization of a novel series of selective imidazonaphthyridine COT kinase inhibitors with unprecedented nanomolar potency for the inhibition of TNFalpha in a whole blood assay using primary human monocytes (PBMCs). Pharmacological profiling in vivo revealed a high level of metabolism of these compounds in rats which has been demonstrated to be predominantly attributed to aldehyde oxidase (AO)-mediated degradation. Thanks to the very low activity of AO in the liver of dog, the selected candidate 30 displayed a significant blood exposure in dogs. Pharmacodynamic evaluation of this compound in dogs using the IL-1beta-dependent uric acid-induced synovitis model showed a clear prevention of the inflammation-driven lameness. Taken together, the described imidazonaphthyridine compounds potently and selectively inhibit Cot kinase in primary human cell types in vitro and ameliorate inflammatory pathologies in vivo, further supporting the notion that Cot is an appropriate therapeutic target for inflammatory diseases.

Item Type:	Article
Keywords:	Cot kinase, Tpl2, MAP3K8, imidazoquinolines, TNFalpha, aldehyde oxidase
Date Deposited:	06 Sep 2016 00:45
Last Modified:	06 Sep 2016 00:45
URI:	https://oak.novartis.com/id/eprint/28871