Abstract：
:From a series of small fragments that was designed to probe the histamine H(4) receptor (H(4)R), we previously described quinoxaline-containing fragments that were grown into high affinity H(4)R 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 H(4)R 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 H(4)R inverse agonists (pK(i) = 8.12 and 7.57, respectively). Interestingly, both compounds also possess considerable affinity for the human histamine H(1) receptor (H(1)R) and therefore represent a novel class of dual action H(1)R/H(4)R ligands, a profile that potentially leads to added therapeutic benefit. Compounds from this novel series of quinazolines are antagonists at the rat H(4)R and were found to possess anti-inflammatory properties in vivo in the rat.
journal_name
J Med Chemjournal_title
Journal of medicinal chemistryauthors
Smits RA,de Esch IJ,Zuiderveld OP,Broeker J,Sansuk K,Guaita E,Coruzzi G,Adami M,Haaksma E,Leurs Rdoi
10.1021/jm800876bsubject
Has Abstractpub_date
2008-12-25 00:00:00pages
7855-65issue
24eissn
0022-2623issn
1520-4804pii
10.1021/jm800876bjournal_volume
51pub_type
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