title: Discovery of quinazolines as histamine H4 receptor inverse agonists using a scaffold hopping approach.
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.
authors.affiliation: Department of Pharmacochemistry, Faculty of Exact Sciences, Leiden/Amsterdam Center for Drug Research, Division of Medicinal Chemistry, Vrije Universiteit Amsterdam, De Boelelaan 1083, 1081 HV Amsterdam, The Netherlands.
authors.forename: Rogier A
authors.initials: RA
authors.lastname: Smits
authors.forename: Iwan J P
authors.initials: IJ
authors.lastname: de Esch
authors.forename: Obbe P
authors.initials: OP
authors.lastname: Zuiderveld
authors.forename: Joachim
authors.initials: J
authors.lastname: Broeker
authors.forename: Kamonchanok
authors.initials: K
authors.lastname: Sansuk
authors.forename: Elena
authors.initials: E
authors.lastname: Guaita
authors.forename: Gabriella
authors.initials: G
authors.lastname: Coruzzi
authors.forename: Maristella
authors.initials: M
authors.lastname: Adami
authors.forename: Eric
authors.initials: E
authors.lastname: Haaksma
authors.forename: Rob
authors.initials: R
authors.lastname: Leurs
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000737:chemistry; D002626:Chemistry, Pharmaceutical / Q000379:methods; D015195:Drug Design; D017442:Histamine Agonists / Q000737:chemistry*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D020128:Inhibitory Concentration 50; D007700:Kinetics; D008956:Models, Chemical; D008958:Models, Molecular; D008968:Molecular Conformation; D011799:Quinazolines / Q000737:chemistry*; D051381:Rats; D043562:Receptors, G-Protein-Coupled / Q000819:agonists*; D011968:Receptors, Histamine; D000074040:Receptors, Histamine H4
chemical_list: D000893:Anti-Inflammatory Agents; C418607:HRH4 protein, human; D017442:Histamine Agonists; D011799:Quinazolines; D043562:Receptors, G-Protein-Coupled; D011968:Receptors, Histamine; D000074040:Receptors, Histamine H4