Novel CXCR3 antagonists with a piperazinyl-piperidine core

Identification of Overlapping but Differential Binding Sites for the High-Affinity CXCR3 Antagonists NBI-74330 and VUF11211

“…4, A, C, and E). The importance of the S-ethyl moiety on the piperazine core was proven by various substitutions that showed a preference for a small apolar group over larger or polar moieties (McGuinness et al, 2009;Shao et al, 2011). This implies that rotation of the pyridine and the piperidine rings with respect to the piperazine ring are restricted and that there is limited space around the ethyl moiety.…”

“…4, A, C, and E). Finally, modification of the amide moiety by removal or repositioning of the nitrogen atom indicated a role for hydrogen bonding of the nitrogen atom (610-fold difference in affinity) (McGuinness et al, 2009;Shao et al, 2011). Removal of the hydroxyl moiety from the residues Y60 1.39 , S304 7.39 , or Y308 7.43 showed that none of them specifically formed an interaction with the amide moiety of VUF11211.…”

“…AMG487 was even assessed in clinical trials for treatment of psoriasis, but was discontinued after a phase IIa trial ). Moreover, a piperazinyl-piperidine compound class with high-affinity CXCR3 ligands has been disclosed by Schering-Plough (now Merck Sharp & Dohme, Whitehouse Station, NJ) (McGuinness et al, 2006(McGuinness et al, , 2009Shao et al, 2011). This compound series is effective in rodent models of CXCR3-associated disease, including transplant rejection and rheumatoid arthritis (Jenh et al, 2012).…”

Pharmacological Characterization of [3H]VUF11211, a Novel Radiolabeled Small-Molecule Inverse Agonist for the Chemokine Receptor CXCR3

“…As VUF11211 had proven to be a reliable and high-affinity tool compound (McGuinness et al, 2009;Scholten et al, 2014) and showed good potency in antagonizing CXCL11 function (confirmed by the CRE and BRET assays), we decided to explore its use as radiolabel. Several synthetic approaches in which the tritium was introduced during the existing synthesis of enantiopure VUF11211 (McGuinness et al, 2009;Scholten et al, 2014) were considered and some subjected to initial unlabeled trials, but eventually all were considered not to be attractive because of the lack of required 3 H reagents or because the conceived labeling reaction could, in theory, erode the enantiomeric excess. Eventually, we settled on outsourcing the radiolabeling of enantiopure VUF11211 itself to PerkinElmer Health Sciences.…”

“…In view of the potential therapeutic interest in CXCR3 blockade in diseases like rheumatoid arthritis and allograft rejection (Wijtmans et al, 2011), many different drug discovery programs have yielded several distinct chemical classes of small-molecule compounds, including antagonists as well as a few agonists (Wijtmans et al, 2008(Wijtmans et al, , 2011, such as the 8-azaquinazolinone compounds from Amgen Inc. (AMG487, (R)-N- (1-(3-(4-ethoxyphenyl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)ethyl)-N-(pyridin-3-ylmethyl)-2-(4-trifluoromethoxy)phenyl)acetamide; Washington, D.C.) and Neurocrine Biosciences pyrimidin-2-yl)ethyl)-2-(4-fluoro-3-(trifluoromethyl)phenyl)-N-(pyridin-3-ylmethyl)acetamide; San Diego, CA), which bind to CXCR3 with affinities in the nanomolar range (Heise et al, 2005;Johnson et al, 2007;Verzijl et al, 2008). Moreover, a piperazinyl-piperidine compound class containing ligands with nanomolar CXCR3 affinities was reported by Schering Plough (now Merck Sharp & Dohme, Kenilworth, NJ) (Mcguinness et al, 2009;Kim et al, 2011;Shao et al, 2011;Nair et al, 2014).…”