The Scripps Research Institute

Youseung Shin

Theodore M Kamenecka

Marcel Koenig

Yuanjun He

Patrick Griffin

Anne-Laure Blayo

Alice Asteian

Brent R Lyda

Naresh Kumar

Thomas Burris

The invention provides small molecule modulators of retinoic acid receptor-related orphan receptors such as ROR&#x3b1;, ROR&#x3b2;, or ROR&#x3b3;, of formula with the variable atoms as defined herein and Rcomprising a hydroxyl- or alkoxyl-substituted fluoroalkyl group. Compounds of the invention can be effective modulators at concentrations ineffective to act on LXR receptors, or on other nuclear receptors, or other biological targets. Methods of modulation the RORs and methods of treating metabolic disorders, immune disorders, cancer, and CNS disorders wherein modulation of an ROR is medically indicated are also provided.

Modulators of the nuclear hormone receptor ROR

The invention provides molecular entities that bind with high affinity to PPARG (PPAR&#x3b3;), 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.

N-benzylindole modulators of PPARG

The invention provides molecular entities that bind with high affinity to PPARG (PPAR&#x3b3;), 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

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Jupiter, FL, United States of America

Youseung Shin