1003463-89-5Relevant academic research and scientific papers
Discovery of quinazolines as histamine H4 receptor inverse agonists using a scaffold hopping approach
Smits, Rogier A.,De Esch, Iwan J. P.,Zuiderveld, Obbe P.,Broeker, Joachim,Sansuk, Kamonchanok,Guaita, Elena,Coruzzi, Gabriella,Adami, Maristella,Haaksma, Eric,Leurs, Rob
, p. 7855 - 7865 (2008)
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 (pKi ) 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.
