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.

Synthesis and QSAR of quinazoline sulfonamides as highly potent human histamine H4 receptor inverse agonists / Smits, R. A.; Adami, Maristella; Istyastono, E. P.; Zuiderveld, O. P.; VAN DAM, C. M. E.; DE KANTER, F. J. J.; Jongejan, A.; Coruzzi, G.; Leurs, R.; DE ESCH, I. J. P.. - In: JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0022-2623. - 53:(2010), pp. 2390-2400. [10.1021/jm901379s]

Synthesis and QSAR of quinazoline sulfonamides as highly potent human histamine H4 receptor inverse agonists

ADAMI, Maristella;
2010-01-01

Abstract

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.
2010
Synthesis and QSAR of quinazoline sulfonamides as highly potent human histamine H4 receptor inverse agonists / Smits, R. A.; Adami, Maristella; Istyastono, E. P.; Zuiderveld, O. P.; VAN DAM, C. M. E.; DE KANTER, F. J. J.; Jongejan, A.; Coruzzi, G.; Leurs, R.; DE ESCH, I. J. P.. - In: JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0022-2623. - 53:(2010), pp. 2390-2400. [10.1021/jm901379s]
File in questo prodotto:
File Dimensione Formato  
Prof. Adami JMEDCHEM 2010.pdf

non disponibili

Tipologia: Documento in Post-print
Licenza: NON PUBBLICO - Accesso privato/ristretto
Dimensione 1.07 MB
Formato Adobe PDF
1.07 MB Adobe PDF   Visualizza/Apri   Richiedi una copia

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11381/2331983
Citazioni
  • ???jsp.display-item.citation.pmc??? ND
  • Scopus 120
  • ???jsp.display-item.citation.isi??? 113
social impact