Discovery and optimization of a series of quinazolinone-derived antagonists of CXCR3

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

“…3C; Table 1). The quinazolinone nitrogen atoms and associated positive partial charge on the 7-position of the ring are important for CXCR3 antagonism (Johnson et al, 2007; WT 100 6 0 9.7 6 0.1 7.8 6 0.0 7.2 6 0.1 TM1 Y60…”

“…In this study, we aimed to elucidate the binding mode of two high-affinity CXCR3 ligands from the 8-azaquinazolinone and the piperazinyl-piperidine class using site-directed mutagenesis complemented with in silico modeling of CXCR3. We show that NBI-74330, from the azaquinazolinone class from Amgen (Heise et al, 2005;Johnson et al, 2007), mainly binds to TMS1, whereas a chlorobenzyl derivative of the piperazinyl-piperidine class disclosed by Merck (McGuinness et al, 2006), with one of the highest CXCR3 affinities [named VUF11211; (S)-5-chloro-6-(4-(1-(4-chlorobenzyl)piperidin-4-yl)-3-ethylpiperazin-1-yl)-N-ethylnicotinamide] , binds to both TMS1 and TMS2 (Fig. 1).…”

“…shown to bind CXCR3 with nanomolar affinities (Heise et al, 2005;Johnson et al, 2007;Verzijl et al, 2008), and are effective in animal models of disease (Walser et al, 2006;van Wanrooij et al, 2008). AMG487 was even assessed in clinical trials for treatment of psoriasis, but was discontinued after a phase IIa trial ).…”

Noncompetitive Antagonism and Inverse Agonism as Mechanism of Action of Nonpeptidergic Antagonists at Primate and Rodent CXCR3 Chemokine Receptors

“…Several classes of small-molecule compounds targeting CXCR3 have recently been described, including 4-N-aryl-[1,4]diazepane ureas (Cole et al, 2006), 1-aryl-3-piperidin-4-yl-urea derivatives (Allen et al, 2007), quinazolin-4-one, 3H-pyrido [2,3-d]pyrimidin-4-one derivatives (Heise et al, 2005;Storelli et al, 2005;Johnson et al, 2007;Storelli et al, 2007), and the above-mentioned quaternary ammonium anilide TAK-779 (Gao et al, 2003). So far, no detailed information is available on the molecular mechanism of action of these small-molecule antagonists at the CXCR3 receptor, despite the general notion that small molecule ligands probably will not have overlapping binding sites with the chemokines, which are supposed to bind mainly to the N terminus and extracellular receptor loops (Murphy et al, 2000).…”

Sequential Metabolism of AMG 487, a Novel CXCR3 Antagonist, Results in Formation of Quinone Reactive Metabolites That Covalently Modify CYP3A4 Cys239 and Cause Time-Dependent Inhibition of the Enzyme

“…(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 (AMG 487) is a potent and selective CXCR3 antagonist that exhibited good oral bioavailability and robust in vivo biological activity in a preclinical model of cellular recruitment (Johnson et al, 2007). In a single ascending dose phase 1 clinical study (suspension dosing), AMG 487 displayed favorable human pharmacokinetics characterized by near-proportional increases in AUC and C max exposure over a dose range of 25 to 1100 mg (Floren et al, 2003).…”