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Research Results of Luye Pharma’s Next-Generation VMAT2 Inhibitor LY03015 Published in European Journal of Medicinal Chemistry

2021 / 09 / 28 Publisher:Luye Life Sciences Group
Research results from a study into Luye Pharma’s in-house developed LY03015, a next-generation vesicular monoamine transporter 2 (VMAT2) inhibitor, were recently published in the European Journal of Medicinal Chemistry, an authoritative international journal with a high impact factor, published by the French Société de Chimie Thérapeutique.
screenshot of the published article
VMAT2 is essential for synaptic transmission of all biogenic amines in the brain, including serotonin, norepinephrine, histamine, and dopamine (DA). Given its crucial role in the neurophysiology and pharmacology of the central nervous system (CNS), VMAT2 is recognized as an important therapeutic target for various neurological disorders such as tardive dyskinesia (TD) and Huntington’s disease (HD), among others.

LY03015 is an innovative new-generation VMAT2 inhibitor developed by Luye Pharma on the company’s New Chemical Entity / New Therapeutic Entity (NCE/NTE) Technology Platform. During the development, researchers designed and synthesized a novel series of dihydrotetrabenazine (DTBZ) derivative analogs for evaluation and found that compound 13e (LY03015) showed a high binding affinity for VMAT2, with excellent inhibition of DA uptake.

In addition to its high in vitro activity, 13e showed promising drug-like properties, with good liver microsome stability and robust in vivo pharmacokinetic properties. Compared with the marketed VMAT2 inhibitors for TD and HD, such as tetrabenazine (TBZ), deutetrabenazine and valbenazine (VBZ), 13e is expected to reduce risks of serious adverse effects such as depression and suicide due to off-target effects. Consistent with the improved pharmacokinetics, its favourable prolonged half-life may enable less frequent daily administrations. Moreover, good brain penetration, lower distribution in the heart tissue and reduced effect on hERG current when compared to VBZ may enable administration at lower dosages, with fewer side effects (e.g., QTc prolongation). The results suggest that 13e might be a promising candidate for TD and HD treatment, with better safety and efficacy profiles.

Key findings: 
  • DTBZ is the major active metabolite of TBZ in vivo and shows a high VMAT2 binding activity. Researchers chose DTBZ as the lead compound and designed DTBZ derivative analogs with improved binding affinity toward VMAT2 through an SAR study. Of these analogs, 13e (LY03015) presented more significant VMAT2-binding affinity (IC50=5.13 nM) than did DTBZ.
  • The in vitro [3H]DA uptake assay in the rat striatal synaptosomes showed that 13e was more potent in [3H]DA uptake inhibition (IC50=6.04 nM) than did DTBZ.
  • Microsome stability and DMPK studies showed that 13e was more stable than DTBZ in human liver microsomes (T1/2=161.2 min; CLint(liver)=8.6 mL/min/kg) in addition to its excellent biochemical and cytostatic activity.
  • In the PK study on male Sprague Dawley (SD) rats after a single oral dosing of the compound, 13e demonstrated excellent pharmacokinetic properties with slower systemic clearance (CL=3.2 L/h/kg) than DTBZ (CL=4.47 L/h/kg), good absorption after oral administration and favorable plasma elimination half-life (T1/2=2.29 h).
  • The study on 13e’s effect on rats’ locomotor activity showed that after oral dosing of the compound, 13e seemed to be significantly more effective than DTBZ in reducing the locomotion (64.7% v.s. 48.4%, P < 0.05), indicating that it is centrally active.
  • Distribution patterns of 13e, VBZ and DTBZ in brain and heart tissues showed that at 2h after dosing, concentration of 13e in the brain was 2-fold higher than that of DTBZ (metabolite of VBZ). Meanwhile, the brain/blood ratio of 13e was 2.21 after 6h administration. This indicated good brain penetration of compound 13e, which is consistent with the effect of 13e in reducing locomotion in rats. Notably, because the distribution of VBZ in the heart tissue may contribute to the increased risk of QT interval prolongation, in this regard the concentration of 13e in the heart was only about half that of VBZ at 6h after administration. In addition, 13e had much less effect on hERG current than VBZ (IC50 =6.51 μM v.s. 1.7 μM).
  • The drug-drug interaction assessment looked at 13e’s potential inhibition on cytochrome P450: 13e was tested up to100 μM and no significant inhibition on CYP activities (CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4) was observed.

“The results demonstrate LY03015’s high binding affinity for VMAT2 and excellent inhibition of DA uptake, indicating its potential clinical value with improved efficacy and safety profiles compared with similar drugs on the market,” said Dr. Tian Jingwei, corresponding author of the article, Vice President of the Non-Clinical Research Department and Head of the New Drug Discovery Department of Luye Pharma Group. “CNS disorders such as TD and HD severely impact patients’ ability to reintegrate into society, leading to a heavy disease burden. To address these urgent clinical needs, we are accelerating the start of clinical studies of LY03015 in China and the U.S. in a bid to provide patients with new treatment options as early as possible.” 

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