MTX115325

• CAT Number: I040512
• CAS Number: 2750895-97-5
• Molecular Formula: C18H16N6O2
• Molecular Weight: 348.36
• Purity: ≥95%
• Synonyms: (3aR,4R,6aR)-1-[5-(2-cyanopyridin-4-yl)-1,3-oxazole-2-carbonyl]-4-methyl-2,3,3a,4,6,6a-hexahydropyrrolo[2,3-c]pyrrole-5-carbonitrile
• InChI: InChI=1S/C18H16N6O2/c1-11-14-3-5-24(15(14)9-23(11)10-20)18(25)17-22-8-16(26-17)12-2-4-21-13(6-12)7-19/h2,4,6,8,11,14-15H,3,5,9H2,1H3/t11-,14-,15+/m1/s1
• InChIKey: LBHXWJUYDOSAAH-DFBGVHRSSA-N
• SMILES: CC1C2CCN(C2CN1C#N)C(=O)C3=NC=C(O3)C4=CC(=NC=C4)C#N

MTX115325 (Example 1) is an orally active, brain-penetrating USP30 inhibitor (IC50=12 nM) with neuroprotective activity. MTX115325 increases ubiquitination (EC50=32 nM) of the mitochondrial outer membrane protein TOM20 (a USP30 substrate), increasing mitophagy. MTX115325 prevents dopaminergic neuron loss and preserves striatal dopamine[1].
MTX115325 (37 nM-1 μM; 72 h) shows promotion of mitochondrial autophagy in SH-SY5Y cells[1].
MTX115325 (10 nM-1 μM; 90 min) promotes ubiquitination of TOM20 and inhibits USP30 activity in both HeLa cells and YFP-Parkin overexpressing HeLa cells[1].
MTX115325 (i.g.; 15 mg/kg and 50 mg/kg; twice daily for 10 weeks) reduces phosphorylated S129-αSyn levels and decreases the total area of GFAP staining in AAV-A53T-SNCA Mouse Model, indicating lower astrocyte activation[1].
MTX115325 (i.g.; 10 mg/kg; single dose) demonstrates excellent oral bioavailability (98%) and good CNS penetration with a brain partition coefficient (Kpu,u) of approximately 0.4[1].
MTX115325 (i.g.; single dose) has a Cmax of 7546.9 ng/mL at 15 mg/kg and a Cmax of 16374.3 ng/mL at 50 mg/kg. At a 50 mg/kg dosage, the drug concentration consistently remained above the EC50 for TOM20 ubiquitination[1].

Reference

[1]. Fang TZ et al. Knockout or inhibition of USP30 protects dopaminergic neurons in a Parkinson’s disease mouse model. Nat Commun. 2023 Nov 13;14(1):7295.
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