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

Hit optimization of the class of quinazoline containing histamine H ₄ 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)quinazoline4-amino)-N- phenylethanesulfonamide (54) (pk_i = 8.31 ± 0.10) revealed it to have anti-inflammatory activity in an animal model of acute inflammation.