American Chemical Society
jm901379s_si_001.pdf (214.55 kB)

Synthesis and QSAR of Quinazoline Sulfonamides As Highly Potent Human Histamine H4 Receptor Inverse Agonists

Download (214.55 kB)
journal contribution
posted on 2010-03-25, 00:00 authored by Rogier A. Smits, Maristella Adami, Enade P. Istyastono, Obbe P. Zuiderveld, Cindy M. E. van Dam, Frans J. J. de Kanter, Aldo Jongejan, Gabriella Coruzzi, Rob Leurs, Iwan J. P. de Esch
Hit optimization of the class of quinazoline containing histamine H4 receptor (H4R) ligands resulted in a sulfonamide substituted analogue with high affinity for the H4R. This moiety leads to improved physicochemical properties and is believed to probe a distinct H4R binding pocket that was previously identified using pharmacophore modeling. By introducing a variety of sulfonamide substituents, the H4R affinity was optimized. The interaction of the new ligands, in combination with a set of previously published quinazoline compounds, was described by a QSAR equation. Pharmacological studies revealed that the sulfonamide analogues have excellent H4R affinity and behave as inverse agonists at the human H4R. In vivo evaluation of the potent 2-(6-chloro-2-(4-methylpiperazin-1-yl)quinazoline-4-amino)-N-phenylethanesulfonamide (54) (pKi = 8.31 ± 0.10) revealed it to have anti-inflammatory activity in an animal model of acute inflammation.