4378-70-5Relevant articles and documents
Synthesis and QSAR of Quinazoline Sulfonamides As Highly Potent Human Histamine H4 Receptor Inverse Agonists
Smits, Rogier A.,Adami, Maristella,Istyastono, Enade P.,Zuiderveld, Obbe P.,Van Dam, Cindy M. E.,De Kanter, Frans J. J.,Jongejan, Aldo,Coruzzi, Gabriella,Leurs, Rob,De Esch, Iwan J. P.
experimental part, p. 2390 - 2400 (2010/09/11)
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) (pki = 8.31 ± 0.10) revealed it to have anti-inflammatory activity in an animal model of acute inflammation.
Probing the structural requirements of peptoids that inhibit HDM2-p53 interactions
Hara, Toshiaki,Durell, Stewart R.,Myers, Michael C.,Appella, Daniel H.
, p. 1995 - 2004 (2007/10/03)
Many cellular processes are controlled by protein-protein interactions, and selective inhibition of these interactions could lead to the development of new therapies for several diseases. In the area of cancer, overexpression of the protein, human double minute 2 (HDM2), which binds to and inactivates the protein p53, has been linked to tumor aggressiveness and drug resistance. In general, inhibition of protein-protein interactions with synthetic molecules is challenging and currently remains a largely uncharted area for drug development. One strategy to create inhibitors of protein-protein interactions is to recreate the three-dimensional arrangement of side chains that are involved in the binding of one protein to another, using a nonnatural scaffold as the attachment point for the side chains. In this study, we used oligomeric peptoids as the scaffold to begin to develop a general strategy in which we could rationally design synthetic molecules that can be optimized for inhibition of protein-protein interactions. Structural information on the HDM2-p53 complex was used to design our first class of peptoid inhibitors, and we provide here, in detail, the strategy to modify peptoids with the appropriate side chains that are effective inhibitors of HDM2-p53 binding. While we initially tried to develop rigid, helical peptoids as HDM2 binders, the best inhibitors were surprisingly peptoids that lacked any helix-promoting groups. These results indicate that starting with rigid peptoid scaffolds may not always be optimal to develop new inhibitors.
