Synthesis of a high specific activity methyl sulfone tritium isotopologue of fevipiprant (NVP‐QAW039)

Luu, Van Tong; Goujon, Jean-Yves; Meisterhans, Christian; Frommherz, Matthias; Bauer, Carsten

doi:10.1002/jlcr.3281

Cited by 10 publications

(5 citation statements)

References 29 publications

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“…This study revealed high levels of DP 1 receptor expression in ciliary epithelium/processes, ciliary muscles, the iris, and the retinal choroid, which was similar to that observed previously using the endogenous ligand [ 3 H]PGD 2 (Matsuo and Cynader, 1993). Selective radiolabeled DP 2 receptor antagonists have been reported: [ 3 H]TRQ11238 (Ulven et al, 2007), [ 3 H 3 ]QAW039 (Luu et al, 2015), and [ 3 H]OC-459 (Sykes et al, 2016) ( Fig. 1; Table 1).…”

Section: B Applications Of Radioligandssupporting

confidence: 86%

Chemical Tools for Studying Lipid-Binding Class A G Protein–Coupled Receptors

et al. 2017

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Cannabinoid, free fatty acid, lysophosphatidic acid, sphingosine 1-phosphate, prostanoid, leukotriene, bile acid, and platelet-activating factor receptor families are class A G protein-coupled receptors with endogenous lipid ligands. Pharmacological tools are crucial for studying these receptors and addressing the many unanswered questions surrounding expression of these receptors in normal and diseased tissues. An inherent challenge for developing tools for these lipid receptors is balancing the often lipophilic requirements of the receptor-binding pharmacophore with favorable physicochemical properties to optimize highly specific binding. In this study, we review the radioligands, fluorescent ligands, covalent ligands, and antibodies that have been used to study these lipid-binding receptors. For each tool type, the characteristics and design rationale along with in vitro and in vivo applications are detailed.

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Section: B Applications Of Radioligandssupporting

confidence: 86%

Chemical Tools for Studying Lipid-Binding Class A G Protein–Coupled Receptors

et al. 2017

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“…The preparation of [ 3 H]-QAW039 has been previously described (see Luu et al, 2015 All radioligand experiments were conducted in 96 deep-well plates in assay binding buffer (Hanks' balanced salt solution containing 10 mM HEPES, 1% dimethylsufoxide (DMSO), and 0.02% pluronic acid, pH 7.4) at 37°C. In all cases, nonspecific binding was determined in the presence of 3 mM AZD-1981, a selective CRTh2 antagonist.…”

Section: Compoundsmentioning

confidence: 99%

Fevipiprant (QAW039), a Slowly Dissociating CRTh2 Antagonist with the Potential for Improved Clinical Efficacy

et al. 2016

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Here we describe the pharmacologic properties of a series of clinically relevant chemoattractant receptor-homologous molecules expressed on T-helper type 2 (CRTh2) receptor antagonists, including fevipiprant (NVP-QAW039 or QAW039), which is currently in development for the treatment of allergic diseases. min 21 and 0.048 minute 21 , respectively. Importantly, the k off of QAW039 (half-life 5 14.4 minutes) was .7-fold slower than the slowest reference compound tested, AZD-1981. In functional studies, QAW039 behaved as an insurmountable antagonist of PGD 2 -stimulated [35 S]-GTPgS activation, and its effects were not fully reversed by increasing concentrations of PGD 2 after an initial 15-minute incubation period. This behavior is consistent with its relatively slow dissociation from the human CRTh2 receptor.In contrast for the other ligands tested this time-dependent effect on maximal stimulation was fully reversed by the 15-minute time point, whereas QAW039's effects persisted for .180 minutes. All CRTh2 antagonists tested inhibited PGD 2 -stimulated human eosinophil shape change, but importantly QAW039 retained its potency in the whole-blood shape-change assay relative to the isolated shape change assay, potentially reflective of its relatively slower off rate from the CRTh2 receptor. QAW039 was also a potent inhibitor of PGD 2 -induced cytokine release in human Th2 cells. Slow CRTh2 antagonist dissociation could provide increased receptor coverage in the face of pathologic PGD 2 concentrations, which may be clinically relevant.

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“…For flash chromatography, in process TLC control, radio‐detection of [ 3 H]CDZ173, determination of the specific activity by MS, open access LC/MS, and service‐MS of intermediates and final products, the same hard ware equipment was used as described in detail in the experimental part of a publication from the isotope lab unit . For GC‐MS analytics of the bis‐halogenated pyridines 16 – 18 , a Waters GTC GC/MS accurate mass instrument was used.…”

Section: Methodsmentioning

confidence: 99%

Design of A Metabolically Stable Tritium‐Tracer of the PI3Kδ‐Inhibitor CDZ173 (Leniolisib) as a Tool to Study Liver Metabolites

Bauer

Luu

Eggimann³

et al. 2018

Helvetica Chimica Acta

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In this disclosure, we summarize the preliminary metabolic profiling of the PI3Kδ inhibitor CDZ173 (leniolisib, 1a) obtained from incubations of the unlabeled compound and the synthesis of its metabolically stable tritium isotopologue 1b used for metabolite structure confirmation. Access to 1b was achieved when a halogenated precursor was subject to Hal/3H‐exchange. Hence, [3H]CDZ173 with specific activity 630 GBq/mmol, HPLC‐RA 97% and ee = 99.2% was obtained. Synthetic key to the precursor was using a bis‐halo‐pyridine in a Pd‐catalyzed mono‐amination of the tetrahydropyrido‐pyrimidine core. Stereochemistry of the synthetic precursors were confirmed by X‐ray analysis of the unlabeled bis‐halo‐pyridines and chiral HPLC of the tritiated material. The correct position of tritium label in the target, was confirmed by 3H‐NMR difference spectroscopy. Besides, we report on the validation of the radiotracer as a tool for pre‐clinical ADME in incubations with hepatocytes. Based on this data, we present a quantitative metabolite profile of leniolisib which was confirmed by independently synthesized metabolite references. The conformation of CDZ173 was investigated by NMR suggesting two different amide backbones each with specific pyrrolidine puckerings.

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Synthesis of a high specific activity methyl sulfone tritium isotopologue of fevipiprant (NVP‐QAW039)

Cited by 10 publications

References 29 publications

Chemical Tools for Studying Lipid-Binding Class A G Protein–Coupled Receptors

Chemical Tools for Studying Lipid-Binding Class A G Protein–Coupled Receptors

Fevipiprant (QAW039), a Slowly Dissociating CRTh2 Antagonist with the Potential for Improved Clinical Efficacy

Design of A Metabolically Stable Tritium‐Tracer of the PI3Kδ‐Inhibitor CDZ173 (Leniolisib) as a Tool to Study Liver Metabolites

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