Pyridazinone PARP7 Inhibitor With Improved Oral Bioavailability
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Solution Overview
Problem
Existing PARP7 inhibitors, such as RBN-2397, suffer from poor pharmacokinetics and low drug exposure, necessitating combination with CYP450 inhibitors for effective anti-tumor activity due to high in vivo clearance rates and low oral bioavailability.
Innovation Solution
Development of a pyridazinone compound with specific structural variations and a preparation method to enhance in vivo and in vitro antitumor activity, including isomers and pharmaceutically acceptable salts, which improve pharmacokinetic properties and bioavailability.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If RBN-2397 is used as a PARP7 inhibitor, then anti-tumor activity is achieved, but in vivo clearance rate is high and oral bioavailability is low
Solution Approach 1:
The patent modifies the chemical structure of RBN-2397 by changing parameters at specific positions (R1-R6 groups, m values) to alter pharmacokinetic properties. This structural parameter change reduces clearance rate and improves bioavailability while maintaining anti-tumor activity, directly resolving the contradiction between efficacy and clearance.
Solution Approach 2:
The patent creates composite molecular structures by combining the core pyridazinone scaffold with various substituent groups (R1-R6). These composite structures exhibit improved pharmacokinetic properties compared to the parent compound, achieving both high anti-tumor activity and reduced clearance.
2Ease of operation
If RBN-2397 is administered alone, then dosing is simplified, but significant anti-tumor effects are not achieved
Solution Approach 1:
The patent develops a self-sufficient inhibitor compound that inherently possesses both high anti-tumor activity and improved pharmacokinetic properties. The modified pyridazinone structure enables single-drug therapy to achieve significant anti-tumor effects without requiring combination with CYP450 inhibitors, making the system self-service capable.
3Reliability
If existing PARP7 inhibitors are used, then PARP7 inhibition is achieved, but pharmacokinetic properties are poor
Solution Approach 1:
The patent systematically modifies structural parameters (R1-R6 groups, m values from 0-3) to optimize the half-life and pharmacokinetic profile. These parameter changes extend the duration of action and improve bioavailability while maintaining potent PARP7 inhibition.
Data Source
AI summary
Disclosed in the present invention are a pyridazinone compound and a preparation method therefor, a pharmaceutical composition thereof, and an application thereof. The pyridazinone compound has a structure as shown in formula (I), and contains an isomer thereof, a pharmaceutically acceptable salt thereof, or a mixture of the isomer and the pharmaceutically acceptable salt. The pyridazinone compound has excellent pharmacokinetic properties in vivo, can also promote the release of immune factors, and in particular, also has excellent antitumor activity in vivo. In addition, the preparation method for the pyridazinone compound is simple and easy.