Structure–activity relationships (SAR) and structure–kinetic relationships (SKR) of pyrrolopiperidinone acetic acids as CRTh2 antagonists

Andrés, Míriam; Buil, Maria Antonia; Calbet, Marta; Casado, Oscar Alonso; Castro, Jordi; Eastwood, Paul; Eichhorn, Peter; Ferrer, Manel; Forns, Pilar; Moreno, Imma; Petit, Silvia; Roberts, Richard S.

doi:10.1016/j.bmcl.2014.08.026

Cited by 18 publications

(11 citation statements)

References 22 publications

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“…Characterization of the drug-target complex lifetime or RT in early phases of the drug discovery and development process might help to improve the prediction of in vivo efficacy and safety 12–15 . Evidence from retrospective studies has shown that several marketed drugs exhibit a long RT on their target 13, 29 , prompting the prospective optimization of both affinity and kinetic properties of compounds for a variety of targets 17, 25, 30–32 . In this regard, 15a was discovered by optimizing a reported lead in the development of MK-0812, a Merck CCR2 antagonist that has failed in clinical trials due to lack of efficacy 33 .…”

Section: Discussionmentioning

confidence: 99%

A novel CCR2 antagonist inhibits atherogenesis in apoE deficient mice by achieving high receptor occupancy

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Zacarı́as

Witte

et al. 2017

Sci Rep

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CC Chemokine Receptor 2 (CCR2) and its endogenous ligand CCL2 are involved in a number of diseases, including atherosclerosis. Several CCR2 antagonists have been developed as potential therapeutic agents, however their in vivo clinical efficacy was limited. In this report, we aimed to determine whether 15a, an antagonist with a long residence time on the human CCR2, is effective in inhibiting the development of atherosclerosis in a mouse disease model. First, radioligand binding assays were performed to determine affinity and binding kinetics of 15a on murine CCR2. To assess the in vivo efficacy, western-type diet fed apoE−/− mice were treated daily with 15a or vehicle as control. Treatment with 15a reduced the amount of circulating CCR2+ monocytes and the size of the atherosclerotic plaques in both the carotid artery and the aortic root. We then showed that the long pharmacokinetic half-life of 15a combined with the high drug concentrations ensured prolonged CCR2 occupancy. These data render 15a a promising compound for drug development and confirms high receptor occupancy as a key parameter when targeting chemokine receptors.

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Section: Discussionmentioning

confidence: 99%

A novel CCR2 antagonist inhibits atherogenesis in apoE deficient mice by achieving high receptor occupancy

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Zacarı́as

Witte

et al. 2017

Sci Rep

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“…35 S]-GTPgS assays performed at room temperature by measuring responses to PGD 2 (100 mM) at fixed time periods following a 60-minute preincubation period with test compounds, allowing antagonist t 1/2 values to be estimated by fitting an exponential decay curve to the PGD 2 responses observed over time (Andrés et al, 2014). Although these results enabled a rank order of residence time to be established, the use of an accumulation assay mean the dissociation t ½ values are likely to be overestimated.…”

Section: Discussionmentioning

confidence: 99%

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

Sykes

Bradley

Riddy

et al. 2016

Molecular Pharmacology

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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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“…We and others have described that CRTh2 antagonists can have slow dissociation kinetics from the receptor [37][38][39] and this was our first hypothesis to explain the observed unsurmountable behavior of our compound.…”

Section: Discussionmentioning

confidence: 63%

Pharmacological characterization of CRTh2 antagonist LAS191859: Long receptor residence time translates into long-lasting in vivo efficacy

Calbet

Andrés

Armengol

et al. 2016

Pharmacological Research

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Structure–activity relationships (SAR) and structure–kinetic relationships (SKR) of pyrrolopiperidinone acetic acids as CRTh2 antagonists

Cited by 18 publications

References 22 publications

A novel CCR2 antagonist inhibits atherogenesis in apoE deficient mice by achieving high receptor occupancy

A novel CCR2 antagonist inhibits atherogenesis in apoE deficient mice by achieving high receptor occupancy

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

Pharmacological characterization of CRTh2 antagonist LAS191859: Long receptor residence time translates into long-lasting in vivo efficacy

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