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 (H(4)R) ligands resulted in a sulfonamide substituted analogue with high affinity for the H(4)R. This moiety leads to improved physicochemical properties and is believed to probe a distinct H(4)R binding pocket that was previously identified using pharmacophore modeling. By introducing a variety of sulfonamide substituents, the H(4)R 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 H(4)R affinity and behave as inverse agonists at the human H(4)R. In vivo evaluation of the potent 2-(6-chloro-2-(4-methylpiperazin-1-yl)quinazoline-4-amino)-N-phenylethanesulfonamide (54) (pK(i) = 8.31 +/- 0.10) revealed it to have anti-inflammatory activity in an animal model of acute inflammation.
Smits
Rogier A
RA
Griffin Discoveries BV, Department of Medicinal Chemistry, Room P-246, De Boelelaan 1083, 1081 HV Amsterdam, The Netherlands.
Adami
Maristella
M
Istyastono
Enade P
EP
Zuiderveld
Obbe P
OP
van Dam
Cindy M E
CM
de Kanter
Frans J J
FJ
Jongejan
Aldo
A
Coruzzi
Gabriella
G
Leurs
Rob
R
de Esch
Iwan J P
IJ
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D001667:Binding, Competitive; D002351:Carrageenan; D004487:Edema / Q000139:chemically induced / Q000517:prevention & control; D006801:Humans; D007700:Kinetics; D008956:Models, Chemical; D015394:Molecular Structure; D021281:Quantitative Structure-Activity Relationship; D011799:Quinazolines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D043562:Receptors, G-Protein-Coupled / Q000819:agonists* / Q000378:metabolism; D011968:Receptors, Histamine / Q000378:metabolism; D000074040:Receptors, Histamine H4; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*
D000893:Anti-Inflammatory Agents; C418607:HRH4 protein, human; D011799:Quinazolines; D043562:Receptors, G-Protein-Coupled; D011968:Receptors, Histamine; D000074040:Receptors, Histamine H4; D013449:Sulfonamides; D002351:Carrageenan