Piperidyl amides as novel, potent and orally active mGlu5 receptor antagonists with anxiolytic-like activity

High throughput screening led to the identification of nicotinamide derivative 2 as a structurally novel mGluR5 antagonist. Optimization of the modular scaffold led to the discovery of 16m, a compound with high affinity for mGluR5 and excellent selectivity over other glutamate receptors. Compound 16m exhibits a favorable PK profile in rats, robust anxiolytic-like effects in three different animal models of fear and anxiety, as well as a good PK/PD correlation

The Crystal structure of the cancer osaka thyroid kinase reveals an unexpected kinase domain fold

Macrophages are important cellular effectors in innate immune responses and play a major role in autoimmune disorders such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). Cancer Osaka Thyroid (COT) kinase, also known as mitogen-activated protein kinase kinase kinase 8 (MAP3K8) and tumor progression locus 2 (Tpl-2), is a Serine-Threonine (ST) kinase and is a key regulator in the production of proinflammatory cytokines in macrophages. Due to its pivotal role in immune biology, COT kinase has been identified as an attractive target for pharmaceutical research that is directed at the discovery of orally available, selective and potent inhibitors for the treatment of autoimmune disorders. The production of monomeric, recombinant COT kinase has proven to be very difficult and issues with solubility and stability of the enzyme have hampered the discovery and optimization of potent and selective inhibitors. We developed a protocol for the production of recombinant human COT kinase that yields pure and highly active enzyme in sufficient yields for biochemical and structural studies. The quality of the enzyme allowed us to establish a robust in vitro phosphorylation assay for the efficient biochemical characterization of COT kinase inhibitors and to determine the X-ray co-crystal structures of the COT kinase domain in complex with two ATP-binding site inhibitors. The structures presented in this publication reveal two distinct ligand binding modes and a unique kinase domain architecture that has not been observed previously. The glycine-rich loop contains a 15 amino acid insert that forms a β-hairpin structure and partially covers the ATP-binding site cleft, which – together with the structurally versatile active site – significantly impacts the design of potent, low-molecular weight COT inhibitors

Discovery of imidazoquinolines as a novel class of potent, selective and in vivo efficacious COT kinase inhibitors

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