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

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Abstract
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.

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