Discovery of 7‐Aryl‐Substituted (1,5‐Naphthyridin‐4‐yl)ureas as Aurora Kinase Inhibitors

Abstract

As part of our research projects to identify new chemical entities of biological interest, we developed a synthetic approach and the biological evaluation of (7-aryl-1,5-naphthyridin-4-yl)ureas as a novel class of Aurora kinase inhibitors for the treatment of malignant diseases based on pathological cell proliferation. 1,5-Naphthyridine derivatives showed excellent inhibitory activities toward Aurora kinases A and B, and the most active compound, 1-cyclopropyl-3-[7-(1-methyl-1H-pyrazol-4-yl)-1,5-naphthyridin-4-yl]urea (49), displayed IC₅₀ values of 13 and 107 nM against Aurora kinases A and B, respectively. In addition, the selectivity toward a panel of seven cancer-related protein kinases was highlighted. In vitro ADME properties were also determined in order to rationalize the difficulties in correlating antiproliferative activity with Aurora kinase inhibition. Finally, the good safety profile of these compounds imparts promising potential for their further development as anticancer agents.

Lead compound bearing caffeic scaffold induces EGFR suppression in solid tumor cancer cells

“…Urea was the selected linker to replace ester function in CAPE because urea moiety contains both hydrogen bond donors and hydrogen bond acceptors, so it is prone to the formation of hydrogen bond. Several modified urea derivatives demonstrated diverse array of anti-proliferative properties (Li et al, 2010;Guagnano et al, 2011;Goffin et al, 2012;Defaux et al, 2014) e.g. sorafenib.…”

Synthetic Strategies, Reactivity and Applications of 1,5-Naphthyridines

“…Initially, it furnished the corresponding enamine 18 in good yields. Ring formation was accomplished by heat-assisted intramolecular cyclization in Dowtherm A or diphenyl ether and the subsequent decarboxylation led to the formation of 8-hydroxy-1,5-naphthyridine 19h ( Scheme 6 ) [ 32 ]. Similarly, in the synthesis of some heteroleptic platinum complexes (FPtXND) bearing 4-hydroxy-1,5-naphthyridine the use of Meldrum’s acid was also the method of choice using substituted triethyl orthoformate to introduce a substituent at the 8 position of the ring ( 19a , c , e – g , Scheme 6 ) [ 33 ].…”

“…In the synthesis of 1,5-naphthyridin-2-yl ureas 222 and 223 , azaheterocyclic amines 220 were reacted with various isocyanates 221 , in pyridine at reflux or in two steps in the presence of triphosgene, trimethylamine and then adding the desired amine ( Scheme 90 ) [ 10 , 32 ].…”

“…In 2014, new chemical entities of biological interest, such as 7-aryl-1,5-naphthyridin-4-ylureas appeared showing excellent inhibitory activities toward Aurora kinases A and B for the treatment of malignant diseases based on pathological cell proliferation [ 32 ]. In this study, the most active compound, 1-cyclopropyl-3-[7-(1-methyl-1 H -pyrazol-4-yl)-1,5-naphthyridin-4-yl]urea 277 ( Figure 9 ), displayed IC 50 values of 107 and 13 nM against Aurora kinases A, and B, respectively.…”

N‐Difluorocyclopropyl‐Substituted Pyrazoles: Synthesis and Reactivity

“…While a number of papers describe synthetic approaches to the compounds having a gem ‐difluorocyclopropyl group attached to the carbon atom, as well as their chemical transformations,, the corresponding N ‐substituted analogues are much less studied. Most of them referred to the parent gem ‐difluorocyclopropylamine ( 5 ) or its derivatives (Scheme );, it should be noted that similar aliphatic amines (e.g. 6 ) were reported to have limited stability .…”