Composition for LRRK2 inhibition containing a thienopyrimidine derivative as an active ingredient

Parkinson's disease candidate drug targeting LRRK2 kinase inhibition via a thieno[3,2-d]pyrimidine-2,4-diamine scaffold

This technology features novel thienopyrimidine derivatives—or their salts—incorporating an anilino group at the 2-position and an alkyl or phenyl amino group at the 4-position of a thieno[3,2-d]pyrimidine scaffold, as well as compositions for LRRK2 inhibition using these as active ingredients. These derivatives inhibit LRRK2 kinase activity and are used for the prevention and treatment of LRRK2-related diseases, including Parkinson's disease.

Current Parkinson's treatments like L-dopa, dopamine receptor agonists, and anticholinergics only manage symptoms rather than addressing the root cause, requiring continuous use. Long-term L-dopa use leads to reduced efficacy and dyskinesia, while anticholinergics cause autonomic and psychiatric side effects, making them difficult to use in elderly patients. Surgical options like deep brain stimulation are invasive and costly, and while some LRRK2 inhibitors have been reported, none have reached clinical application.

This technology utilizes derivatives of Formula 1, combining R1–R4 substituents, NH or N-methyl for X, and carbonyl, amide, or reverse-amide linkers to inhibit abnormal LRRK2 kinase activity. It presents 18 specific compounds, including N-benzyl benzamide derivatives, and formulates pharmaceutical compositions at concentrations of 4–80 mg/kg. Applications extend beyond Parkinson's, dementia, and L-dopa-induced dyskinesia to include LRRK2-linked inflammatory bowel diseases like Crohn's and ulcerative colitis, as well as various cancers. As a disease-modifying therapy targeting the underlying mechanism, it offers an alternative to dopamine replacement by blocking LRRK2 overactivity, which leads to α-synuclein aggregation and neuronal death.

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Key Features:

• Thienopyrimidine derivatives of Formula 1 where R3 is C1-C4 alkyl or phenyl, X is NH or N-methyl, and Y is carbonyl, amide, or reverse-amide
• Thienopyrimidine compounds selected from 18 types, including N4-methyl-N2-phenylthienopyrimidine-2,4-diamine and N-benzyl benzamide derivatives
• Pharmaceutical compositions for treating LRRK2-related diseases such as Parkinson's, dementia, and L-dopa-induced dyskinesia, containing the thienopyrimidine derivative at a concentration of 4 to 80 mg/kg
• Health functional food compositions for improving LRRK2-related diseases and reagent compositions for LRRK2 inhibition, containing the thienopyrimidine derivative as an active ingredient

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This invention was developed with support from the Meta-Receptome Control Research Center of the Ministry of Science and ICT.

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