A class of pyrazolopyridine compounds linked by an azatetra-cyclic ring or a pharmaceutically acceptable salt thereof and applications thereof

By designing pyrazolopyridine compounds linked by aza-4-membered rings, optimizing their molecular structure, and employing lung-targeted drug delivery, the problem of central nervous system inhibition by PDE10A inhibitors was solved, achieving highly selective treatment of peripheral tissue diseases and reducing the risk of adverse reactions.

CN119707962BActive Publication Date: 2025-11-11SUN YAT SEN UNIV
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Patent Information

Application Number
CN202411843520.9
Authority / Receiving Office
CN · China
Patent Type
Patents(China)
Current Assignee / Owner
Filing Date
2024-12-14
Publication Date
2025-11-11
Estimated Expiration
2044-12-14

AI Technical Summary

Technical Problem

Existing PDE10A inhibitors tend to have a significant inhibitory effect on the central nervous system when treating peripheral tissue diseases, leading to frequent adverse events and making it difficult to achieve selective treatment of peripheral tissues.

Method used

A class of pyrazolopyridine compounds with a nitrogen-containing four-membered ring were designed. By modifying the molecular structure, the permeability to the blood-brain barrier was reduced. The lung tissue-targeted drug delivery method was adopted to reduce the first-pass effect of oral administration, thereby reducing the accumulation of the compound in the brain and its inhibitory effect on the central nervous system.

Benefits of technology

It achieves highly selective inhibition of PDE10A, significantly reduces the inhibitory effect on the central nervous system, reduces the occurrence of adverse events, and effectively treats peripheral tissue diseases such as myocardial hypertrophy, cardiac dysfunction, diabetes, hypertension, renal impairment, pulmonary inflammation and pulmonary fibrosis, immune regulation disorders, and cancer.

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Abstract

This invention discloses a class of pyrazolopyridine compounds linked by an aza-four-membered ring, or pharmaceutically acceptable salts thereof, and their applications. These compounds can serve as novel, highly selective PDE10A inhibitors for the treatment of peripheral tissue diseases, including: myocardial hypertrophy and cardiac dysfunction (heart failure), diabetes, hypertension, renal impairment and renal fibrosis, pulmonary inflammation and pulmonary fibrosis, immune dysregulation, and cancers (colon cancer, ovarian cancer, and lung cancer). Two strategies are employed to achieve high selectivity for PDE10A inhibition while simultaneously reducing the inhibitory effect on the central nervous system. First, molecular structure modification: structural optimization of the aza-four-membered ring-linked pyrazolopyridine compounds, such as increasing the ratio of N, O, and S atoms in the molecular structure to increase the polar surface area and reduce lipophilicity; and introducing hydrophilic groups to increase water solubility, thereby reducing the permeability of the compound to the blood-brain barrier (BBB). Second, targeted drug delivery to lung tissue via pharmaceutical formulation.
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