The invention provides molecular entities that bind with high affinity to PPARG (PPAR.gamma.), and 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. Side effects such as significant weight gain, edema, impairment of bone growth or formation, or cardiac hypertrophy, or any combination thereof, can be avoided in the mammal 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.

Kamenecka; Theodore Mark

Griffin; Patrick R.

Koenig; Marcel

Asteian; Alice

Blayo; Anne-Laure

He; Yuanjun

Shin; Youseung

The Scripps Research Institute

N-benzylindole modulators of PPARG

The invention provides molecular entities that bind with high affinity to PPARG (PPAR.gamma.), 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.

N-biphenylmethylindole modulators of PPARG

hyperinsulinism

edema

hyperinsulinism/edema

N-benzylindole modulators of PPARG

N-biphenylmethylindole modulators of PPARG

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