Discovery and characterization of GSK256073, a non-flushing hydroxy-carboxylic acid receptor 2 (HCA2) agonist

Sprecher, Dennis L.; Maxwell, Miles; Goodman, Joanne; White, B.P.; Tang, Chi-Man; Boullay, Valérie; Gouville, Anne-Charlotte de

doi:10.1016/j.ejphar.2015.01.051

Cited by 21 publications

(20 citation statements)

References 26 publications

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“…These improvements in glucose tolerance were attributed to an increase in insulin sensitivity with an associated decrease in insulin concentrations. Encouragingly, no flushing or adverse effects on the gastrointestinal tract were observed (Sprecher et al, 2015). However, recent data from a randomized 12-week trial revealed that GSK256073 did not meet its primary end point in reducing HbA1c compared with placebo (Dobbins et al, 2015).…”

Section: Hydroxycarboxylic Acid Receptor 2 (Gpr109a)mentioning

confidence: 99%

G Protein–Coupled Receptors Targeting Insulin Resistance, Obesity, and Type 2 Diabetes Mellitus

Riddy¹,

Delerive²,

Summers³

et al. 2017

Pharmacol Rev

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G protein-coupled receptors (GPCRs) continue to be important discovery targets for the treatment of type 2 diabetes mellitus (T2DM). Many GPCRs are directly involved in the development of insulin resistance and -cell dysfunction, and in the etiology of inflammation that can lead to obesity-induced T2DM. This review summarizes the current literature describing a number of well-validated GPCR targets, but also outlines several new and promising targets for drug discovery. We highlight the importance of understanding the role of these receptors in the disease pathology, and their basic pharmacology, which will pave the way to the development of novel pharmacological probes that will enable these targets to fulfill their promise for the treatment of these metabolic disorders.

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Section: Hydroxycarboxylic Acid Receptor 2 (Gpr109a)mentioning

confidence: 99%

G Protein–Coupled Receptors Targeting Insulin Resistance, Obesity, and Type 2 Diabetes Mellitus

Riddy¹,

Delerive²,

Summers³

et al. 2017

Pharmacol Rev

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“…GSK256073 was developed by GlaxoSmithKline as a potent and selective GPR109A agonist with 10 times the potency of niacin [ 70 ]. Consistent with GPR109A agonism, animal studies confirmed acute, dose-dependent, peak FFA, and TG suppression up to 90 %, with much lesser NASTy effects.…”

Section: Niacin Receptor Mimeticsmentioning

confidence: 99%

Niacin Alternatives for Dyslipidemia: Fool’s Gold or Gold Mine? Part II: Novel Niacin Mimetics

Goel

Dunbar

2016

Curr Atheroscler Rep

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Two cardiovascular outcome trials established niacin 3 g daily prevents hard cardiac events. However, as detailed in part I of this series, an extended-release (ER) alternative at only 2 g nightly demonstrated no comparable benefits in two outcome trials, implying the alternative is not equivalent to the established cardioprotective regimen. Since statins leave a significant treatment gap, this presents a major opportunity for developers. Importantly, the established regimen is cardioprotective, so the pathway is likely beneficial. Moreover, though effective, the established cardioprotective regimen is cumbersome, limiting clinical use. At the same time, the ER alternative has been thoroughly discredited as a viable substitute for the established cardioprotective regimen. Therefore, by exploiting the pathway and skillfully avoiding the problems with the established cardioprotective regimen and the ER alternative, developers could validate cardioprotective variations facing little meaningful competition from their predecessors. Thus, shrewd developers could effectively tap into a gold mine at the grave of the ER alternative. The GPR109A receptor was discovered a decade ago, leading to a large body of evidence commending the niacin pathway to a lower cardiovascular risk beyond statins. While mediating niacin’s most prominent adverse effects, GPR109A also seems to mediate anti-lipolytic, anti-inflammatory, and anti-atherogenic effects of niacin. Several developers are investing heavily in novel strategies to exploit niacin’s therapeutic pathways. These include selective GPR109A receptor agonists, niacin prodrugs, and a niacin metabolite, with encouraging early phase human data. In part II of this review, we summarize the accumulated results of these early phase studies of emerging niacin mimetics.

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“…GSK256073 is a novel, potent, full agonist of the GPR109A receptor that is approximately 100‐fold more selective for the GPR109A (HM74A) receptor than for the HM74 receptor (pEC 50 = 7.5 ± 0.04 and pEC 50 = 5.6 ± 0.04, respectively). The chemical structure of GSK256073 has been reported in a recent study on the discovery and characterization of GSK256073 …”

mentioning

confidence: 99%

“…Previous studies in healthy volunteers have shown that GSK256073, at doses as low as 5 mg resulted in exposures that produced suppression of NEFA levels of similar magnitude to those produced by niacin, but were associated with very mild or no flushing . It has been speculated that certain molecules that activate the HM74a receptor drive an alternative signaling pathway that limits prostaglandin expression when compared with niacin .…”

mentioning

confidence: 99%

“…It has been speculated that certain molecules that activate the HM74a receptor drive an alternative signaling pathway that limits prostaglandin expression when compared with niacin . Sprecher et al demonstrated this for GSK256073 based on a reduction of Guinea pig ear flushing despite equivalent niacin‐induced NEFA reductions. Interestingly, most likely related to its long half‐life (∼10‐15 hours), the NEFA reductions produced by GSK256073 were prolonged compared with those produced by niacin.…”

mentioning

confidence: 99%

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A Randomized, Placebo‐Controlled Trial to Assess the Effects of 8 Weeks of Administration of GSK256073, a Selective GPR109A Agonist, on High‐Density Lipoprotein Cholesterol in Subjects With Dyslipidemia

Olson

Mahar

Haws

et al. 2019

Clinical Pharm in Drug Dev

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GPR109A (HM74A), a G‐protein‐coupled receptor, is hypothesized to mediate lipid and lipoprotein changes and dermal flushing associated with niacin administration. GSK256073 (8‐chloro‐3‐pentyl‐1H‐purine‐2,6[3H,7H]‐dione) is a selective GPR109A agonist shown to suppress fatty acid levels and produce mild flushing in short‐term clinical studies. This study evaluated the effects of GSK256073 on lipids in subjects with low high‐density lipoprotein cholesterol (HDLc). Subjects (n = 80) were randomized (1:1:1:1) to receive GSK256073 5, 50, or 150 mg/day or matching placebo for 8 weeks. The primary end point was determining the GSK256073 exposure‐response relationship for change from baseline in HDLc. No significant exposure response was observed between GSK256073 and HDLc levels. GSK256073 did not significantly alter HDLc levels versus placebo, but rather revealed a trend at the 150‐mg dose for a nonsignificant decrease in HDLc (‐6.31%; P = .12) and an increase in triglycerides (median, 24.4%; 95% confidence interval, 7.3%‐41.6%). Flushing was reported in 21%, 25%, and 60% of subjects (5, 50, and 150 mg, respectively) versus 24% for placebo. Results indicated that selective activation of the GPR109A receptor with GSK256073 did not produce niacin‐like lipid effects. These findings add to the increasing evidence that niacin‐mediated lipoprotein changes occur predominantly via GPR109A‐independent pathways.

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Discovery and characterization of GSK256073, a non-flushing hydroxy-carboxylic acid receptor 2 (HCA2) agonist

Cited by 21 publications

References 26 publications

G Protein–Coupled Receptors Targeting Insulin Resistance, Obesity, and Type 2 Diabetes Mellitus

G Protein–Coupled Receptors Targeting Insulin Resistance, Obesity, and Type 2 Diabetes Mellitus

Niacin Alternatives for Dyslipidemia: Fool’s Gold or Gold Mine? Part II: Novel Niacin Mimetics

A Randomized, Placebo‐Controlled Trial to Assess the Effects of 8 Weeks of Administration of GSK256073, a Selective GPR109A Agonist, on High‐Density Lipoprotein Cholesterol in Subjects With Dyslipidemia

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