Discovery of quinazolines as histamine H4 receptor inverse agonists using a scaffold hopping approach.
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.
Smits
Rogier A
RA
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.
de Esch
Iwan J P
IJ
Zuiderveld
Obbe P
OP
Broeker
Joachim
J
Sansuk
Kamonchanok
K
Guaita
Elena
E
Coruzzi
Gabriella
G
Adami
Maristella
M
Haaksma
Eric
E
Leurs
Rob
R
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
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