University of California

University of Washington

Unity Biotechnology, Inc.

Autobahn Therapeutics, Inc.

Optikira LLC

Bradley J Backes

Dustin James Maly

Feroz R Papa

Thomas W Von Geldern

Scott A Oakes

Bing Chen

Gayani Perera

Likun Wang

Charles S Craik

Jonathan A Ellman

Jennifer Harris

Richard McCulloch Keenan

Baoku He

Jason Harris

Jean-Christophe Poupon

George Hynd

Jonathan Mark Sutton

Charles Reynolds

Jamie Knight

Ben Whittaker

Jon Sutton

Compounds are provided having the structure of Formula (I) or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R, R, X, X, Y, and Yare as defined herein. Such compounds function as thyromimetics and have utility for treating diseases such as neurodegenerative disorders and fibrotic diseases. Pharmaceutical compositions containing such compounds are also provided, as are methods of their use and preparation.

Thyromimetics

Disclosed herein are, inter alia, compounds modulating Inositol-Requiring Enzyme 1α (IRE1α) and IRE1β activity and methods of use thereof for treating IRE1α-mediated and IRE1β-mediated disorders.

Substituted pyrimidines as IRE1 kinase inhibitors

Disclosed herein, inter alia, are compounds for inhibiting IRE1α and uses thereof.

IRE1α inhibitors and uses thereof

Disclosed herein, inter alia, are substituted quinazolin-2-amines and isoquinolin-3-amines for inhibiting IRE1&#x3b1; and uses thereof.

IRE1&#x3b1; inhibitors and uses thereof

Compounds are provided having the structure of Formula (I): or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein X, X, and Rare as defined herein. Such compounds function as thyromimetics and have utility for treating diseases such as neurodegenerative disorders and fibrotic diseases. Pharmaceutical compositions containing such compounds are also provided, as are methods of their use and preparation.

Compounds are provided having the structure of Formula (I): or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein A, X, X, Q, R, Rand n are as defined herein. Such compounds function as thyromimetics and have utility for treating diseases such as neurodegenerative disorders and fibrotic diseases. Pharmaceutical compositions containing such compounds are also provided, as are methods of their use and preparation.

Provided herein, inter alia, are substituted imidazo[1,5-&#x3b1;]pyrazine compounds, compositions and methods for treating or preventing an IRE1&#x3b1;-related disease or disorder. In certain embodiments, the disease or disorder is selected from the group consisting of a neurodegenerative disease, a demyelinating disease, cancer, an eye disease, a fibrotic disease, and diabetes. 

Substituted imidazo[1,5-a]pyrazines for IRE1 inhibition

Described herein, inter alia, are certain substituted imidazo[1,5-a]pyrazines of formula (I) and methods of using the same for modulating the activity of Ire1. 

Substituted imidazo[1,5-a]pyrazines for modulation of IRE1

Compounds represented by Formula (I) and (II) and salts thereof are described herein. The compounds or salts of Formula (I) and (II) may be used to treat senescence-associated diseases and disorders. 

Acylsulfonamide derivatives for treating senescence-associated diseases and disorders

Described herein, inter alia, are certain substituted imidazolopyrazines of formula (I) and methods of using the same for modulating the activity of Ire1. 

Substituted imidazolopyrazine compounds and methods of using same

This invention provides a method for enantioselective synthesis of cis-imidazolines and related structures through chiral resolution. A chiral acid is used to separate enantiomeric precursors of the cis-imidazolines from a racemic mixture by selective crystallization. Both enantiomers can be cyclized into the desired cis-imidazoline by complementary pathways. Compounds can be synthesized according to the invention with an enantiomeric excess as high as 99%. Cis-imidazolines such as Nutlin-3a prepared according to this invention may be used for treating cancer, killing senescent cells, or treating senescence-associated conditions.

Chiral synthesis method for producing cis-imidazoline compounds for pharmaceutical use

Described herein, inter alia, are compositions and methods of using the same for modulating the activity of Ire1 using for example, substituted imidazopyrazine compounds.

Substituted imidazo[1,5-a]pYRAZINES for modulation of IRE1

A method is presented for the preparation and use of fluorogenic peptide substrates that allows for the configuration of general substrate libraries to rapidly identify the primary and extended specificity of enzymes, such as proteases. The substrates contain a fluorogenic-leaving group, such as 7-amino-4-carbamoylmethyl-coumarin (ACC). Substrates incorporating the ACC leaving group show comparable kinetic profiles as those with the traditionally used 7-amino-4-methyl-coumarin (AMC) leaving group. The bifunctional nature of ACC allows for the efficient production of single substrates and substrate libraries using solid-phase synthesis techniques.

Fluorogenic materials and uses thereof

A method is presented for the preparation and use of fluorogenic peptide substrates that allows for the configuration of general substrate libraries to rapidly identify the primary and extended specificity of enzymes, such as proteases. The substrates contain a fluorogenic-leaving group, such as 7-amino-4-carbamoylmethyl-coumarin (ACC). Substrates incorporating the ACC leaving group show comparable kinetic profiles as those with the traditionally used 7-amino-4-methyl-coumarin (AMC) leaving group. The bifunctional nature of ACC allows for the efficient production of single substrates and substrate libraries using solid-phase synthesis techniques. The approximately 3-fold increased quantum yield of ACC over AMC permits reduction in enzyme and substrate concentrations. As a consequence, a greater number of substrates can be tolerated in a single assay, thus enabling an increase in the diversity space of the library. Soluble positional protease substrate libraries of 137,180 and 6,859 members, possessing amino acid diversity at the P4-P3-P2-P1 and P4-P3-P2 positions, respectively, were constructed. Employing this screening method the substrate specificities of a diverse array of proteases were profiled, including the serine proteases thrombin, plasmin, factor Xa, uPA, tPA, granzyme B, trypsin, chymotrypsin, human neutrophil elastase, and the cysteine proteases papain and cruzain. The resulting profiles create a pharmacophoric portrayal of the proteases allowing for the design of selective substrates and potent inhibitors.

Growing community of inventors

San Diego, CA, United States of America

Bradley J Backes