Aryl extensions of thienopyrimidinones as fibroblast growth factor receptor 1 kinase inhibitors

Abstract

Optimization of thienopyrimidinone derivatives as FGFR1 kinase inhibitors is being pursued. The present results confirm predictions of computational modeling that an aryl subtituent can be introduced at the 2-position in strucure 3. The substituent is anticipated to project deeper into the binding site and provide opportunities for enhanced activity and selectivity. The most potent analog reported here, 13, has a 4-hydroxyphenyl substituent and yields an IC 50 of 6 μM for inhibition of phosphorylation by FGFR1 kinase. It was also found that the western anisolecontaining substituent in 3 can be replaced by a propionic acid group with no loss in potency and with potentially significant gains in pharmacologically relevant properties. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As affect service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. In the course of studies to identify new FGFR1 kinase inhibitors, we discovered two inhibitors 1 and 2, a benzylidene derivative of pseudothiohydantoin and a thienopyrimidinone derivative, by structure-based virtual screening followed by initial lead optimization.19 1 and 2 inhibit phosphorylation by FGFR1 kinase with IC 50 values of 23 and 1.9 μM, respectively. The pseudothiohydantoin 1 was also found to be an inhibitor of EGFR, Src, and InsR kinases with IC 50 values of 10-56 μM. The thienopyrimidinone 2 was found to inhibit EGFR and Src kinases with IC 50 values of 2.4 and 1.9 μM, while it did not inhibited InsR. Thus, little selectivity was observed with these compounds. In an effort to develop more potent and selective FGFR1 kinase inhibitors, the thienopyrimidinones were chosen for further optimization. Keywords NIH Public AccessA structure from docking calculations19 for the 21-μM inhibitor 3 complexed with FGFR1 kinase is illustrated in Figure 2A. Formation of two hydrogen bonds between the amide fragment in the pyrimidinone ring of 3 and Ala564 in the hinge region is anticipated. The tricyclic core of thienopyrimidinone 3 is spatially limited to the ATP binding site, and the western end of the inhibitor is solvent exposed. Exploration eastward, deeper into the active site, is expected to be potentially more fruitful, especially for selectivity owing to variation among kinases in this area. In the eastern end of 3 (see Figures 1 and 2A), position 1 is solvent exposed and substitutions here should have limited effect on modulating activity. However, the de novo ligand-design program BOMB20 , 21 (Biomolecular and Organic Molecule Builder) was used to consider introduction of substituents at positions 2-4 on the ligand in the binding site; the utilized protein coordinates came fro...

Characterization of Biaryl Torsional Energetics and its Treatment in OPLS All-Atom Force Fields

“…3 Arylpyrimidinone substructures have also been featured in some of our FGFR1 kinase inhibitors. 2 Furthermore, 6-aryl-pyridinones have been reported as orally active inhibitors of the EP3 receptor, 30 and as core structures of different non-peptidic inhibitors of human leukocyte elastase 31 and interleukin-1β converting enzyme. 32 Thus, ten 6-aryl-pyridinones were also selected for parameterization ( 21 – 30 in Figure 3).…”

“…There is good agreement between the computed and crystallographic results, especially since the gas and solid phases are being compared. Three systems (2,9,11) prefer to be nearly planar, while the other three (10,12,21) are twisted by about 30°. Though patterns are discussed more below, it can be noted that the twisted ones have either the full complement of four ortho hydrogens or, for 12, clear electrostatic repulsion in the planar form.…”

“…In addition, as part of an ongoing effort to develop improved inhibitors of the von Hippel–Lindau E3 ubiquitin ligase/HIF-1α interaction, we have been exploring 6-arylpyridinones as alternatives to previous biaryl cores . Arylpyrimidinone substructures have also been featured in some of our FGFR1 kinase inhibitors . Furthermore, 6-aryl-pyridinones have been reported as orally active inhibitors of the EP3 receptor, and as core structures of different nonpeptidic inhibitors of human leukocyte elastase and interleukin-1β converting enzyme .…”

“…Brameld et al analyzed the Prous database and found that biphenyl and 5-phenyl-1 H -tetrazole were the third and seventh most frequently observed cores in compounds entering phase I clinical trials . Our laboratory has also had high interest in biaryls since they arise regularly in our inhibitor design efforts, e.g., for fibroblast growth factor receptor 1 (FGFR1) kinase, the von Hippel–Lindau E3 ubiquitin ligase/HIF-1α interaction, and Plasmodium falciparum macrophage migration inhibitory factor (MIF) . Biaryl cores also emerged in the development of agonists of human MIF-CD74 binding .…”

Thieno[2,3-d]pyrimidinedione derivatives as antibacterial agents

“…While there have been reports of antibacterial activity for structurally unrelated thieno-pyrimidinones (see Introduction), the mechanism of action of those agents has never reported. Thieno-pyrimidines and thieno-pyrimidinediones have been reported as inhibitors of proteases[28], kinases[29–31] and folate utilizing enzymes[8, 9, 32, 33] suggesting that the mechanism of action of our agent could be due to inhibition of a specific protein. The inhibition of folate utilizing enzymes (i.e.…”