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

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.

Metabolism of c-Met Kinase Inhibitors Containing Quinoline by Aldehyde Oxidase, Electron Donating, and Steric Hindrance Effect

“…5. The meta-O-linked EDGs in XK-469 (2-[4-(7-chloroquinoxalin-2-yl) oxyphenoxy]propanoate) (Anderson et al, 2005;Hutzler et al, 2012) and VU0409106 [3-fluoro-N-(4-methyl-2-thiazolyl)-5-(5-pyrimidinyloxy) benzamide] (Morrison et al, 2012), or the meta-N-linked EDG in example 2, and compounds 20 (Lepri et al, 2017;Cruciani et al, 2018) and 30 (Glatthar et al, 2016) made these compounds more susceptible to AO metabolism (Fig. 5).…”

New Druggable Targets for Rheumatoid Arthritis Based on Insights From Synovial Biology

“…Position of SMI in therapeutic hierarchy of RA has not been strong, with only JAKi in the market and a litany of failed attempts such as MAPK p38i (57). However, the scenario is now improving with preclinical studies of molecules designed to be more specific on targeted cells and pathways, thereby positively tweaking the efficacy-safety profile of small molecule therapy (58)(59)(60)(61)(62). Such efforts are expected to lead to clearing the perpetuating inflammatory damage in the joint and complement efficacy of bDMARDs in order to reset productive immunity.…”

“…Most importantly, MAP3K8 has a unique kinase domain architecture wherein an extended and highly flexible P-loop covers the active site cleft due to a 15 amino acid insert (PDB 5IU2). This feature, not found in other human kinases, exposes a deeper flexible pocket which can be exploited for selective drug design ( 58 ), wherein traditional ATP-mimetic scaffolds may be extended for extra hydrophobic and hydrogen bonding interactions ( Figure 5B ). Although MAP3K8 is a relatively newer target for RA with few SAR inhibitors reported in preclinical studies ( 58 , 138 ), a specific inhibitor, GS-4875, is advancing in clinical animal studies for multiple inflammatory diseases ( 139 ).…”

Efficient Synthesis of Pharmaceutically Relevant Prochiral Heterocyclic Aminoketones

“…Prochiral aminoketones bearing different saturated heterocycles represent an important group of building blocks that can be utilized for the synthesis of active pharmaceutical ingredients containing (optically active) polyamines (such as selective P2X3 receptor antagonist RO-85 for inflammatory pain (1) [1], potential anticancer agent LPA2 (EDG4) antagonists [2], anti-inflammatory Cancer Osaka thyroid (COT) kinase inhibitors [3], potential antimalarial 4-aminoquinoline derivatives [4]), amino alcohols (such as analgesic 5-HT receptor agonists (2) [5]) and oximes (e.g. potential antibacterial agent 3 [6]) ( Fig.…”