Discovery of a second generation agonist of the orphan G-protein coupled receptor GPR119 with an improved profile

Semple, Graeme; Lehmann, Juerg; Wong, Amy; Ren, Albert; Bruce, Marc A.; Shin, Young-Jun; Sage, Carleton R.; Morgan, Michael; Chen, Weichao; Sebring, Kristen; Chu, Zhi-Liang; Leonard, Janet L.; Al-Shamma, Hussein; Grottick, Andrew J.; Du, Fuyong; Liang, Yin; Demarest, Keith T.; Jones, Robert M.

doi:10.1016/j.bmcl.2011.12.092

Cited by 44 publications

(45 citation statements)

References 9 publications

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“…2 and 3), this provides a good response window with which to observe reversal responses. In the absence of a suitable neutral antagonist we used the weak partial agonist ARN-II (ligand 9a in Semple et al (2012)). …”

Section: Evidence For a Role Of Membrane Deposition In Sustained Respmentioning

confidence: 99%

Sustained wash-resistant receptor activation responses of GPR119 agonists

Hothersall

Bussey

Brown

et al. 2015

European Journal of Pharmacology

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G protein-coupled receptor 119 (GPR119) is involved in regulating metabolic homoeostasis, with GPR119 agonists targeted for the treatment of type-2 diabetes and obesity. Using the endogenous agonist oleoylethanolamide and a number of small molecule synthetic agonists we have investigated the temporal dynamics of receptor signalling. Using both a dynamic luminescence biosensor-based assay and an endpoint cAMP accumulation assay we show that agonist-driven desensitization is not a major regulatory mechanism for GPR119 despite robust activation responses, regardless of the agonist used. Temporal analysis of the cAMP responses demonstrated sustained signalling resistant to washout for some, but not all of the agonists tested. Further analysis indicated that the sustained effects of one synthetic agonist AR-231,453 were consistent with a role for slow dissociation kinetics. In contrast, the sustained responses to MBX-2982 and AZ1 appeared to involve membrane deposition. We also detect wash-resistant responses to AR-231,453 at the level of physiologically relevant responses in an endogenous expression system (GLP-1 secretion in GLUTag cells). In conclusion, our findings indicate that in a recombinant expression system GPR119 activation is sustained, with little evidence of pronounced receptor desensitization, and for some ligands persistent agonist responses continue despite removal of excess agonist. This provides novel understanding of the temporal responses profiles of potential drug candidates targetting GPR119, and highlights the importance of carefully examining the the mechanisms through which GPCRs generate sustained responses.

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Section: Evidence For a Role Of Membrane Deposition In Sustained Respmentioning

confidence: 99%

Sustained wash-resistant receptor activation responses of GPR119 agonists

Hothersall

Bussey

Brown

et al. 2015

European Journal of Pharmacology

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“…7,8 Following this, we recently reported a 5-fluoro-4,6-dialkoxypyrimidine series (e.g., 2) that exhibited improved in vitro agonist efficacy and possessed reduced CYP2C9 inhibitory potential. 9 Thus far, our prototypical GPR119 agonists have had a central pyrimidine pharmacophore as a preferred structural feature.…”

Section: Introductionmentioning

confidence: 95%

Discovery of a novel trans-1,4-dioxycyclohexane GPR119 agonist series

Han

Narayanan

Kim

et al. 2015

Bioorganic & Medicinal Chemistry Letters

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“…In the anesthetized Guinea Pig, treatment with APD597 (hGPR119 EC50 = 46 nM) did not produce any dose-related, statistically significant effects on mean arterial blood pressure (MAP), heart rate (HR) or on the electrocardiogram (ECG) at cumulative doses up to 5 mg/kg IV, when compared to vehicle controls. Preliminary safety studies in rat (14-day) and dog (7-day) revealed no obvious liabilities that would prevent further development [34]. …”

Section: Arena Pharmaceuticalsmentioning

confidence: 99%

“…ReleaseID=320208). Early clinical candidates for GPR119 derived from the tool compound AR231453 and the structure of the major hydroxylated metabolite of APD668 [34].…”

Section: Arena Pharmaceuticalsmentioning

confidence: 99%

“…To tackle the CYP2C9 inhibition we elected to focus primarily on our alternative scaffold, as exemplified by 9 ( Figure 5), which generally had significantly lower CYP2C9 inhibition than the pyrazolopyrimidine series (CYP2C9 IC50 for 9 = 5.3 μM) without bringing other obvious liabilities into play [34]. Therefore, they were encouraged that switching to this scaffold may also be the best approach to try to increase the range of possible sites of metabolism, without greatly increasing clearance.…”

Section: Arena Pharmaceuticalsmentioning

confidence: 99%

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