Discovery of Quinazolines as Histamine H₄ Receptor Inverse Agonists Using a Scaffold Hopping Approach

Abstract

From a series of small fragments that was designed to probe the histamine H(4) receptor (H(4)R), we previously described quinoxaline-containing fragments that were grown into high affinity H(4)R ligands in a process that was guided by pharmacophore modeling. With a scaffold hopping exercise and using the same in silico models, we now report the identification and optimization of a series of quinazoline-containing H(4)R compounds. This approach led to the discovery of 6-chloro-N-(furan-3-ylmethyl)2-(4-methylpiperazin-1-yl)quinazolin-4-amine (VUF10499, 54) and 6-chloro-2-(4-methylpiperazin-1-yl)-N-(thiophen-2-ylmethyl)quinazolin-4-amine (VUF10497, 55) as potent human H(4)R inverse agonists (pK(i) = 8.12 and 7.57, respectively). Interestingly, both compounds also possess considerable affinity for the human histamine H(1) receptor (H(1)R) and therefore represent a novel class of dual action H(1)R/H(4)R ligands, a profile that potentially leads to added therapeutic benefit. Compounds from this novel series of quinazolines are antagonists at the rat H(4)R and were found to possess anti-inflammatory properties in vivo in the rat.

Analysis of Multiple Histamine H4 Receptor Compound Classes Uncovers Gαi Protein- and β-Arrestin2-Biased Ligands

“…The hH 4 R ligands that display a clear bias toward ␤-arrestin2 recruitment can be divided into three structural groups: one quinoxaline (VIII, VUF10214) (Smits et al, 2008), one isothiourea (IV, VUF5223) , and four indolecarboxamides (VII, VUF10056, VUF6002, VUF11273, and VUF11012). These compounds are neutral antagonists or inverse agonists for G␣ i protein-dependent signaling but act as agonists in the ␤-arrestin2 recruitment assay.…”

“…In recent years, both industry and academia have discovered and characterized many new hH 4 R ligands, mainly on the basis of hH 4 R binding affinity and specificity (Jablonowski et al, 2003;Terzioglu et al, 2004;Thurmond et al, 2004;Lim et al, 2005Lim et al, , 2006Liu et al, 2008;Smits et al, 2008;Igel et al, 2009;Strakhova et al, 2009;Schneider et al, 2010;Smits et al, 2010). The therapeutic value of such hH 4 R ligands is potentially very interesting, not only for pathologies such as airway inflammation and allergic rhinitis but also for other inflammatory conditions (inflammatory bowel disease and atopic dermatitis) .…”

Interactions of Histamine H1-Receptor Agonists and Antagonists with the Human Histamine H4-Receptor

“…Inverse agonists stabilize the R state of GPCRs and reduce agonist-independent basal G-protein activity (Seifert and Wenzel-Seifert, 2002). Meanwhile, numerous H 4 R antagonists (Jablonowski et al, 2003;Terzioglu et al, 2004;Venable et al, 2005;Smits et al, 2008) and agonists (Hashimoto et al, 2003;Lim et al, 2005;Igel et al, 2009) have been identified. Although thioperamide is commonly used as the reference hH 4 R inverse agonist (Lim et al, 2005;Thurmond et al, 2008), the ligand is actually only a partial inverse agonist .…”

Application of quinazoline and pyrido[3,2-d]pyrimidine templates to design multi-targeting agents in Alzheimer's disease

“…These compounds were synthesized as per previously reported method. 24,26 In a 350 mL round pressure vial 16-18 g urea was heated at 150-155 C till it melted. To the liquid urea solution 0.1 eq.…”