Fluorinated Depsipeptides for Resistant Heartworm Prevention
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
There is a need for more effective antiparasitic agents to treat and prevent infections caused by endoparasites such as Dirofilaria immitis, which has developed resistance to existing macrocyclic lactone drugs.
Innovation Solution
Development of novel cyclic depsipeptide compounds with selective anthelmintic activity against L3 and L4 staged endoparasites, particularly Dirofilaria immitis L4, which are administered to animals to prevent or treat parasitic infections.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If macrocyclic lactone drugs are used for heartworm prevention, then prophylaxis treatment is effective against L3 and L4 larvae, but resistance develops in Dirofilaria immitis populations
Solution Approach 1:
The patent modifies the chemical structure of existing macrocyclic lactones by changing molecular parameters - specifically adding fluorine atoms at specific positions (e.g., 2,4-difluoro substitution pattern) and adjusting ring structures. These parameter changes create new compounds with improved anthelmintic activity that overcome parasite resistance while maintaining the core mechanism of action against L3 and L4 larvae
Solution Approach 2:
The invention creates composite molecular structures by combining the macrocyclic lactone core with additional functional groups (fluorine substituents, modified ring systems). This composite approach generates compounds that retain the parent compound's efficacy while adding resistance-breaking properties through the integrated molecular features
2Reliability
If adulticide treatment is used for mature heartworm infection, then the infection can be treated, but serious adverse side effects occur
Solution Approach 1:
The patent enables preliminary action by effectively killing L3 and L4 larvae before they mature into adult heartworms. This preventive approach eliminates the need for dangerous adulticide treatments, as the modified macrocyclic lactones maintain high efficacy against immature stages while avoiding the toxic effects associated with adult worm destruction
Solution Approach 2:
The invention converts the limitation of not being able to treat mature worms safely into a benefit by enhancing activity against immature stages. The modified compounds' increased potency against L3 and L4 larvae allows complete prevention of mature infection, transforming the therapeutic challenge into a preventive solution that avoids adverse effects
3Productivity
If monthly macrocyclic lactone administration is used, then L3 and L4 larvae are killed and adult worm development is prevented, but increasing lack of efficacy cases are reported
Solution Approach 1:
The patent applies parameter changes by modifying molecular structure (fluorine substitution, ring modifications) to enhance the compounds' intrinsic activity and stability. These changes ensure consistent efficacy in field conditions by improving the drugs' ability to penetrate parasite tissues and maintain potency against resistant populations
Data Source
AI summary
The present invention provides cyclic depsipeptides of Formula (1), stereoisomers thereof, and veterinary acceptable salts thereof wherein each of R1, R2, R3, R4, L1, and L2 are as defined herein. The present invention also contemplates compositions, methods of treatment, and uses as a medicament to treat an animal for an endoparasitic infection with a Formula (1 ) compound.