Discovery of quinazolines as histamine H4 receptor inverse agonists using a scaffold hopping approach

Article abstract of DOI:10.1021/jm800876b

From a series of small fragments that was designed to probe the histamine H₄ receptor (H₄R), we previously described quinoxaline-containing fragments that were grown into high affinity H ₄R ligands in a process that was guided by pharmacophore modeling. With a scaffold hopping exercise and using the same in silico models, we now report the identification and optimization of a series of quinazoline-containing H₄R compounds. This approach led to the discovery of 6-chloro-N-(furan-3-ylmethyl)2-(4-methylpiperazin-1-yl)quinazolin-4-amine (VUF10499, 54) and 6-chloro-2-(4-methylpiperazin-1-yl)-N-(thiophen-2-ylmethyl) quinazolin-4-amine (VUF10497, 55) as potent human H₄R inverse agonists (pK_i ) 8.12 and 7.57, respectively). Interestingly, both compounds also possess considerable affinity for the human histamine H ₁ receptor (H₁R) and therefore represent a novel class of dual action H₁R/H₄R ligands, a profile that potentially leads to added therapeutic benefit. Compounds from this novel series of quinazolines are antagonists at the rat H₄R and were found to possess anti-inflammatory properties in vivo in the rat.