Non-agonist PPARG Modulators Block cdk5 Phosphorylation
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Solution Overview
Problem
Current PPARG agonists used for treating type II diabetes and related conditions often cause significant side effects such as weight gain, edema, and cardiac hypertrophy due to their agonistic activity, which can be detrimental to patients, especially those with pre-existing cardiovascular issues.
Innovation Solution
Development of non-activating (non-agonist) PPARG modulators that inhibit kinase-mediated phosphorylation of PPARG, specifically targeting cdk5-mediated phosphorylation at serine 273, without activating the receptor, thereby avoiding the side effects associated with full and partial agonists.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If PPARG agonists are used to treat type II diabetes, then insulin sensitivity is improved, but significant side effects occur including weight gain, edema, and cardiac hypertrophy
Solution Approach 1:
Instead of using agonists that activate PPARG to improve insulin sensitivity, the invention uses non-agonist modulators that block kinase-mediated phosphorylation of PPARG. This inverted approach achieves the therapeutic benefit of improved glucose homeostasis while avoiding the harmful side effects of receptor activation, including weight gain, edema, and cardiac hypertrophy
Solution Approach 2:
The invention extracts and isolates the specific beneficial action of blocking cdk5-mediated phosphorylation at serine 273 from the overall agonist activity. By designing compounds that specifically inhibit this phosphorylation event without activating the receptor, the harmful side effects are separated from the therapeutic effect
2Productivity
If full and partial agonists of PPARG are administered, then anti-diabetic actions are achieved, but side effects such as weight gain, edema, and cardiac hypertrophy occur
Solution Approach 1:
The invention changes the mode of action parameter from receptor activation (agonism) to phosphorylation inhibition (non-agonist modulation). This parameter change maintains the ability to improve glucose homeostasis and insulin sensitivity while eliminating the side effects associated with receptor activation, thereby decoupling therapeutic efficacy from harmful effects
Data Source
AI summary
The invention provides molecular entities that bind with high affinity to PPARG (PPARĪ³), inhibit kinase-mediated, e.g., cdk5-mediated, phosphorylation of PPARG, but do not exert an agonistic effect on PPARG. Compounds of the invention can be used for treatment of conditions in patients wherein PPARG plays a role, such as diabetes, insulin resistance, impaired glucose tolerance, pre-diabetes, hyperglycemia, hyperinsulinemia, obesity, or inflammation. In methods of treatment of these conditions using a compound of the invention, the compound can avoid producing side effects of significant weight gain, edema, impairment of bone growth or formation, or cardiac hypertrophy, or any combination thereof, in the patient receiving the compound. Methods of preparation of the compounds, bioassay methods for evaluating compounds of the invention as non-agonistic PPARG binding compounds, and pharmaceutical compositions are also provided.