<i>In vitro</i> and <i>in vivo</i> metabolite identification of a novel benzimidazole compound ZLN005 by liquid chromatography/tandem mass spectrometry

Sun, Wenchao; Nguyen, Khoa D.; Fitch, William L.; Banister, Samuel D.; Tang, Hongxiang; Zhang, Xiaolan; Yu, Lewis; Engleman, Edgar G.; Jayakumar, R.

doi:10.1002/rcm.8060

Cited by 11 publications

(4 citation statements)

References 19 publications

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“…Furthermore, early treatment with lasmiditan for 7 consecutive days from day 1 after surgery delayed the onset of mechanical allodynia in SNI rats. A study has indicated that the half-life of ZLN005 is 11.46 ± 0.67 min in rats ( Sun et al, 2018 ). A clinical study indicated that plasma concentrations of lasmiditan peaked at 1.5–2 h post dose, with a terminal half-life of approximately 4 h ( Tsai et al, 2021 ).…”

Section: Discussionmentioning

confidence: 99%

5-HT1F Receptor Agonist Ameliorates Mechanical Allodynia in Neuropathic Pain via Induction of Mitochondrial Biogenesis and Suppression of Neuroinflammation

Zhang

Zhou

et al. 2022

Front. Pharmacol.

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Neuropathic pain is a devastating disease that affects millions of people worldwide. Serotonin (5-hydroxytryptamine, 5-HT) is involved in pain modulation. Several lines of evidence have indicated that 5-HT1F receptor agonists are potent inducers of mitochondrial biogenesis. In this study, we tested the hypothesis that 5-HT1F receptor agonists ameliorate mechanical allodynia in neuropathic pain via the induction of mitochondrial biogenesis and suppression of neuroinflammation. Male Sprague–Dawley rats were used to establish a neuropathic pain model via spared nerve injury (SNI). The paw withdrawal threshold (PWT) was used to evaluate mechanical allodynia. Real-time polymerase chain reaction was used to examine the mitochondrial DNA (mtDNA) copy number. Western blotting and immunofluorescence were used to examine the expression of target proteins. Our results showed that mitochondrial biogenesis was impaired in the spinal cord of rats with SNI. Moreover, activation of PGC-1α, the master regulator of mitochondrial biogenesis, attenuates established mechanical allodynia in rats with neuropathic pain. In addition, the neuronal 5-HT1F receptor is significantly downregulated in the spinal cord of rats with neuropathic pain. Furthermore, the selective 5-HT1F receptor agonist lasmiditan attenuated established mechanical allodynia in rats with neuropathic pain. Finally, lasmiditan (Las) treatment restored mitochondrial biogenesis and suppressed neuroinflammation in the spinal cord of rats with SNI. These results provide the first evidence that lasmiditan ameliorates mechanical allodynia in neuropathic pain by inducing mitochondrial biogenesis and suppressing neuroinflammation in the spinal cord. Inducers of mitochondrial biogenesis may be an encouraging therapeutic option for the management of neuropathic pain.

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Section: Discussionmentioning

confidence: 99%

5-HT1F Receptor Agonist Ameliorates Mechanical Allodynia in Neuropathic Pain via Induction of Mitochondrial Biogenesis and Suppression of Neuroinflammation

Zhang

Zhou

et al. 2022

Front. Pharmacol.

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“…Although activation of PGC-1α can occur through the β-adrenergic receptor (β-AR)/3'-5'-cyclic adenosine monophosphate (cAMP) and AMP-activated protein kinase (AMPK) pathways [33,34], more recent studies have utilized a small, benzimidazole compound ZLN005 to induce PGC-1α expression [35][36][37][38][39][40][41]. Hence, the application of ZLN005 to activate PGC-1α might be an effective approach to promote cardiomyocyte maturation.…”

Section: Agingmentioning

confidence: 99%

PGC-1α activator ZLN005 promotes maturation of cardiomyocytes derived from human embryonic stem cells

Liu

Bai

Guo

et al. 2020

Aging

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INTRODUCTIONHuman cardiovascular diseases continue to cause major health and economic burden worldwide [1,2]. Cardiomyocytes differentiated from human pluripotent stem cells (hPSC-CMs), including both embryonic stem cell-derived cardiomyocytes (hESC-CMs) and induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), provide an enormous potential for the development of tissue engineering, drug screening, and cardiac disease www.aging-us.com

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“…However, this modality is unlikely to soon become widely applicable due to the need for myeloablative conditioning, prolonged and intense follow-up, and off-target potential and cost, which is likely to be between $1 and $2 million for a onetime dose. [42][43][44][45][46] A small molecule like ZLN005, with oral bioavailability 25,47 and effects additive to HU and possibly other HbF inducers, might have more therapeutic potential where SCD is most prevalent.…”

Section: Discussionmentioning

confidence: 99%

Pharmacologic induction of PGC‐1α stimulates fetal haemoglobin gene expression

Sun

Habara

et al. 2022

Br J Haematol

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Summary Sickle cell disease (SCD) is a genetic disorder that affects millions around the world. Enhancement of fetal γ‐globin levels and fetal haemoglobin (HbF) production in SCD patients leads to diminished severity of many clinical features of the disease. We recently identified the transcriptional co‐activator PGC‐1α as a new protein involved in the regulation of the globin genes. Here, we report that upregulation of PGC‐1α by infection with a lentivirus expressing PGC‐1α or by the small‐molecule PGC‐1α agonist ZLN005 in human primary erythroid progenitor CD34+ cells induces both fetal γ‐globin mRNA and protein expression as well as the percentage of HbF‐positive cell (F cells) without significantly affecting cell proliferation and differentiation. We further found that the combination of ZLN005 and hydroxyurea (hydroxycarbamide) exhibited an additive effect on the expression of γ‐globin and the generation of F cells from cultured CD34+ cells. In addition, ZLN005 induced robust expression of the murine embryonic βh1‐globin gene and to a lesser extent, human γ‐globin gene expression in sickle mice. These findings suggest that activation of PGC‐1α by ZLN005 might provide a new path for modulating HbF levels with potential therapeutic benefit in β‐hemoglobinopathies.

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In vitro and in vivo metabolite identification of a novel benzimidazole compound ZLN005 by liquid chromatography/tandem mass spectrometry

Abstract: Using both in vitro and in vivo methods, we elucidated the metabolic pathway of ZLN005. Phase I metabolites with hydroxylation and carboxylation, as well as phase II metabolites with glucuronide, sulfate and glutathione conjugation, were identified.

Cited by 11 publications

References 19 publications

5-HT1F Receptor Agonist Ameliorates Mechanical Allodynia in Neuropathic Pain via Induction of Mitochondrial Biogenesis and Suppression of Neuroinflammation

5-HT1F Receptor Agonist Ameliorates Mechanical Allodynia in Neuropathic Pain via Induction of Mitochondrial Biogenesis and Suppression of Neuroinflammation

PGC-1α activator ZLN005 promotes maturation of cardiomyocytes derived from human embryonic stem cells

Pharmacologic induction of PGC‐1α stimulates fetal haemoglobin gene expression

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