The Scripps Research Institute

University of Florida Research Foundation Inc

Dana-Farber-Cancer Institute Inc.

The Broad Institute, Inc.

The University of Toledo

Ember Therapeutics, Inc.

Patrick Griffin

Theodore M Kamenecka

Marcel Koenig

Yuanjun He

Anne-Laure Blayo

Youseung Shin

Matthew Surman

Steven K Duddy

Alice Asteian

Gavin Rumbaugh

Steve Young

Laszlo Radnai

Courtney Anne Miller

Beata Lecka-Czernik

Stuart L Schreiber

Jeffrey O Saunders

Bruce M Spiegelman

Amy Ripka

Partha Pratim Nag

Pere Puigserver

Joshua A Bittker

Jonathan Z Long

Krystopher Aurigemma

Luis Bedoya

James Shanley

Jason Fisherman

Peter Suzman

Roger Schilling

Brent R Lyda

Naresh Kumar

Thomas Burris

Hua Lin

Kfir Sharabi

Mi Ra Chang

Eric Raabe

Roy Emmerthal

Kurt Oestreicher

Disclosed herein are methods and uses of the polypharmacological modulator SR1903 and related compounds for inhibiting triggering receptor expressed on myeloid cells-1 (TREM-1) and treating diseases and conditions that are related to or mediated by TREM-1, such as inflammatory diseases, autoimmune diseases, metabolic disorders, and castration resistant prostate cancer (CRPC).

Method of inhibiting TREM-1

The invention can provide compounds, analogs of blebbistatin, effective and selective inhibitors of nonmuscle myosin II relative to cardiac myosin II. Compounds can be used in the method of treating a disease, disorder, or medical condition in a patient, comprising modulating myosin II ATPase, such as treatment of substance abuse relapse disorder, or of renal disease, cancer and metastasis, benign prostate hyperplasia, hemostasis or thrombosis, nerve injury including retinal damage, lung fibrosis, liver fibrosis, arthrofibrosis, wound healing, spinal cord injury, periodontitis, glaucoma and immune-related diseases including multiple sclerosis; or wherein the disease, disorder, or medical condition comprises addiction including abuse of or addiction to anything classified as a Substance-Related or Addictive Disorder in the Diagnostic and Statistical Manual of Mental Disorders (DSM), such as, but not limited to, cocaine, opioids, amphetamines, ethanol,/marijuana, nicotine, and activities including gambling. Compounds are of general formula with substituents as defined herein.

Nonmuscle myosin ii inhibitors

The invention can provide compounds, analogs of blebbistatin, effective and selective inhibitors of nonmuscle myosin II relative to cardiac myosin II. Compounds can be used in the method of treating a disease, disorder, or medical condition in a patient, comprising modulating myosin II ATPase, such as treatment of substance abuse relapse disorder, or of renal disease, cancer and metastasis, benign prostate hyperplasia, hemostasis or thrombosis, nerve injury including retinal damage, lung fibrosis, liver fibrosis, arthrofibrosis, wound healing, spinal cord injury, periodontitis, glaucoma and immune-related diseases including multiple sclerosis; or wherein the disease, disorder, or medical condition comprises addiction including abuse of or addiction to anything classified as a Substance-Related or Addictive Disorder in the Diagnostic and Statistical Manual of Mental Disorders (DSM), such as, but not limited to, cocaine, opioids, amphetamines, ethanol, cannabis/marijuana, nicotine, and activities including gambling Compounds are of general formula (I) with substituents as defined herein.

Nonmuscle myosin II inhibitors for substance use relapse

Uncoupling of respiration is a well-recognized process that increases respiration and heat production in cells. Provided herein are chemical uncouplers of respiration that are compounds of Formula (I). Also provided are methods for preventing or treating metabolic disorders and modulating metabolic processes using compound of Formula (I).

Chemical uncouplers of respiration and methods of use thereof

The present invention provides compounds, pharmaceutical compositions and methods for treating and/or preventing a metabolic condition, such as diabetes.

Selective inhibition of gluconeogenic activity

The invention provides methods of treatment of a progressive bone disease, such as osteoporosis, Paget's Disease, multiple myeloma, or hyperparathyroidism, comprising administration of an effective amount of a non-agonist PPARG modulator to a patient afflicted with the disease.

PPARG modulators for the treatment of osteoporosis

PPARG modulators for treatment of osteoporosis

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;), inhibit 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 or obesity. 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-biphenylmethylbenzimidazole modulators of PPARG

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

Patrick Griffin