SCO-267, a GPR40 Full Agonist, Stimulates Islet and Gut Hormone Secretion and Improves Glycemic Control in Humans

Nishizaki, Harunobu; Matsuoka, Osamu; Kagawa, Tetsushi; Kobayashi, Akihiro; Watanabe, Masanori; Moritoh, Yusuke

doi:10.2337/db21-0451

Cited by 20 publications

(18 citation statements)

References 28 publications

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“…In a phase I clinical trial, SCO-267 was safe and well tolerated in healthy participants after single and multiple doses. SCO-267 stimulated insulin and incretin secretion, and robustly improved glucose tolerance in T2D patients after single dose ( Nishizaki et al, 2021 ). No severe treatment emergent adverse events (TEAEs) were reported in the single ascending dose (SAD) and multiple ascending dose (MAD) studies.…”

Section: Clinical Development Of Gpr40 Agonistsmentioning

confidence: 99%

“…No severe treatment emergent adverse events (TEAEs) were reported in the single ascending dose (SAD) and multiple ascending dose (MAD) studies. The most common TEAEs were gastrointestinal effects, including diarrhea, nausea, vomiting and decreased appetite, with a greater extent in groups receiving higher doses of SCO-267 (80 and 320 mg) compared to the placebo group ( Nishizaki et al, 2021 ). SCO-267 is currently in phase II development.…”

Section: Clinical Development Of Gpr40 Agonistsmentioning

confidence: 99%

“…AgoPAM agonist mediated β-cell toxicity also seems to be compound specific. In the preclinical and clinical studies of SCO-267, a GPR40 AgoPAM agonist, no β-cell toxicity had been reported in rats and humans ( Ueno et al, 2019b ; Nishizaki et al, 2021 ). Altogether, GPR40-mediated β-cell toxicity is specific for some AgoPAM agonists but not partial agonists, which has been proven in clinical trials of TAK-875 and no β-cell related adverse effects were reported in chronically treated T2D patients ( Burant et al, 2012 ).…”

Section: Safety Concerns Of Gpr40 Agonists and Possible Mechanismsmentioning

confidence: 99%

“…The GPR40 AgoPAM agonist, in contrast, has demonstrated significant body weight reduction in mouse and rat obese models ( Gorski et al, 2017 ; Ueno et al, 2019b ), indicating the level of increase in incretins is higher than achievable via DPP4 inhibition. In phase 1 clinical trial in T2D patients, SCO-267 increased plasma GLP-1 by 3-5 folds, GIP by 30%, and PYY by 70% after single dose and robustly suppressed glucose excursion in oGTT test ( Nishizaki et al, 2021 ). Therefore, it is highly likely that the gut-restricted GPR40 agonist has the potential to be more efficacious than DPP4 inhibitor to control hyperglycemia in T2D patients, in addition to body weight reduction.…”

Section: Gut-restrictive Gpr40 Agonist For Metabolic Disorders and Be...mentioning

confidence: 99%

“…At this dose, the C max of SCO-267 was around 40-fold lower than TAK-875 to achieve similar efficacy, indicating a possibly higher safety margin of SCO-267 and might show differentiation in terms of liver toxicity ( Ueno et al, 2019b ). SCO-267 demonstrated very good glucose lowering efficacies at 40 and 80 mg doses in phase I trial ( Nishizaki et al, 2021 ), and is currently being developed in phase II trial for T2D. Whether the improvements of SCO-267 in preclinical settings can be translated to patients will be verified in later stage clinical trials, optimizing the potency and PK profile of compounds might be a plausible strategy to increase the safety margin.…”

Section: Emerging Hopes For Gpr40 Agonistsmentioning

confidence: 99%

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Learn from failures and stay hopeful to GPR40, a GPCR target with robust efficacy, for therapy of metabolic disorders

Guan¹,

Xiong²

2022

Front. Pharmacol.

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GPR40 is a class A G-protein coupled receptor (GPCR) mainly expressed in pancreas, intestine, and brain. Its endogenous ligand is long-chain fatty acids, which activate GPR40 after meal ingestion to induce secretion of incretins in the gut, including GLP-1, GIP, and PYY, the latter control appetite and glucose metabolism. For its involvement in satiety regulation and metabolic homeostasis, partial and AgoPAM (Positive Allosteric Modulation agonist) GPR40 agonists had been developed for type 2 diabetes (T2D) by many pharmaceutical companies. The proof-of-concept of GPR40 for control of hyperglycemia was achieved by clinical trials of partial GPR40 agonist, TAK-875, demonstrating a robust decrease in HbA1c (-1.12%) after chronic treatment in T2D. The development of TAK-875, however, was terminated due to liver toxicity in 2.7% patients with more than 3-fold increase of ALT in phase II and III clinical trials. Different mechanisms had since been proposed to explain the drug-induced liver injury, including acyl glucuronidation, inhibition of mitochondrial respiration and hepatobiliary transporters, ROS generation, etc. In addition, activation of GPR40 by AgoPAM agonists in pancreas was also linked to β-cell damage in rats. Notwithstanding the multiple safety concerns on the development of small-molecule GPR40 agonists for T2D, some partial and AgoPAM GPR40 agonists are still under clinical development. Here we review the most recent progress of GPR40 agonists development and the possible mechanisms of the side effects in different organs, and discuss the possibility of developing novel strategies that retain the robust efficacy of GPR40 agonists for metabolic disorders while avoid toxicities caused by off-target and on-target mechanisms.

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Section: Clinical Development Of Gpr40 Agonistsmentioning

confidence: 99%

Section: Clinical Development Of Gpr40 Agonistsmentioning

confidence: 99%

Section: Safety Concerns Of Gpr40 Agonists and Possible Mechanismsmentioning

confidence: 99%

Section: Gut-restrictive Gpr40 Agonist For Metabolic Disorders and Be...mentioning

confidence: 99%

Section: Emerging Hopes For Gpr40 Agonistsmentioning

confidence: 99%

See 3 more Smart Citations

Learn from failures and stay hopeful to GPR40, a GPCR target with robust efficacy, for therapy of metabolic disorders

Guan¹,

Xiong²

2022

Front. Pharmacol.

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Evidence for cytochrome P450 3A4‐mediated metabolic activation of SCO‐267

Li,

Fan

et al. 2024

Biopharm & Drug Disp

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SCO‐267 is a potent G‐protein‐coupled receptor 40 agonist that is undergoing clinical development for the treatment of type 2 diabetes mellitus. The current work was undertaken to investigate the bioactivation potential of SCO‐267 in vitro and in vivo. Three SCO‐267‐derived glutathione (GSH) conjugates (M1–M3) were found both in rat and human liver microsomal incubations supplemented with GSH and nicotinamide adenine dinucleotide phosphate. Two GSH conjugates (M1–M2) together with two N‐acetyl‐cysteine conjugates (M4–M5) were detected in the bile of rats receiving SCO‐267 at 10 mg/kg. The identified conjugates suggested the generation of quinone‐imine and ortho‐quinone intermediates. CYP3A4 was demonstrated to primarily catalyze the bioactivation of SCO‐267. In addition, SCO‐267 concentration‐, time‐, and NADPH‐dependently inactivated CYP3A in human liver microsomes using testosterone as a probe substrate, along with KI and kinact values of 4.91 μM and 0.036 min−1, respectively. Ketoconazole (a competitive inhibitor of CYP3A) displayed no significant protective effect on SCO‐267‐induced CYP3A inactivation. However, inclusion of GSH showed significant protection. These findings revealed that SCO‐267 undergoes a facile CYP3A4‐catalyzed bioactivation with the generation of quinone‐imine and ortho‐quinone intermediates, which were assumed to be involved in SCO‐267 induced CYP3A inactivation. These findings provide further insight into the bioactivation pathways involved in the generation of reactive, potentially toxic metabolites of SCO‐267. Further studies are needed to evaluate the influence of SCO‐267 metabolism on the safety of this drug in vivo.

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Preclinical pharmacokinetics and metabolism study of SCO‐267, a GPR40 full agonist, in beagle dogs using ultra‐high performance liquid chromatography coupled to tandem mass spectrometry

Liu

Xiao

et al. 2023

Biomedical Chromatography

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SCO‐267 is a GPR40 full agonist that has been developed for the treatment of diabetes. To support its preclinical and clinical development, in this study, we developed an ultra‐high performance liquid chromatography tandem mass spectrometric method for the determination of SCO‐267 in dog plasma using cabozantinib as internal standard (IS). The chromatographic separation was obtained on a Waters acquity BEH C18 column (50 × 2.1 mm, i.d., 1.7 μm) and the detection was performed using Thermo TSQ triple quadrupole mass spectrometer with multiple reaction monitoring positive mode at m/z 615.3 > 230.1 for SCO‐267 and m/z 502.5 > 323.3 for IS. The method was validated over the concentration range of 1–2,000 ng/ml with the lower limit of quantification of 1 ng/ml. The selectivity, linearity, precision and accuracy over this range were acceptable. The extraction recovery was more than 88.73% and no matrix effect was observed. SCO‐267 was demonstrated to be stable during the storage and processing period. The new method was successfully applied to the pharmacokinetic study in beagle dogs following a single oral and intravenous administration. The oral bioavailability was 64.34%. In addition, the metabolites from dog liver microsomal incubation and plasma collected after an oral administration were identified by a UHPLC–HRMS method. The biotransformation pathways of SCO‐267 involved oxygenation, O‐demethylation, N‐dealkylation and acyl glucuronidation.

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SCO-267, a GPR40 Full Agonist, Stimulates Islet and Gut Hormone Secretion and Improves Glycemic Control in Humans

Cited by 20 publications

References 28 publications

Learn from failures and stay hopeful to GPR40, a GPCR target with robust efficacy, for therapy of metabolic disorders

Learn from failures and stay hopeful to GPR40, a GPCR target with robust efficacy, for therapy of metabolic disorders

Evidence for cytochrome P450 3A4‐mediated metabolic activation of SCO‐267

Preclinical pharmacokinetics and metabolism study of SCO‐267, a GPR40 full agonist, in beagle dogs using ultra‐high performance liquid chromatography coupled to tandem mass spectrometry

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