Georgia Tech Research Corporation

Emory University

The United States of America As Represented by the Department of Health

James C Powers

Chih-Min Kam

Sheldon W May

Jan Glinski

Maria A Hernandez

Wade Harper

Steve Thornton

Jonathan D Glass

Jerry J Buccafusco

Jozef Oleksyszyn

Josef Oleksyszyn

M A Hernandez

Bogdan Boduszek

Kenneth M Starks

J A Glinski

Thomas F Moran

Mark O Lively, Iii

Zhaozhao Li

Karen Ellis James

Juliana Asgian

Marion Gabriele Gotz

Ahmed Salih Abuelyaman

David N Ku

Louis E Henderson

Zhao Zhao Li

Asli Ovat

Shin Ono

Delwin S Jackson

Liming Ni

Thomas Sayers

Mark J Smyth

Theresa A Wiltrout

Raymond Sowder

Girish S Patil

Der-Lun Chu

Özlem Dogan Ekici

Brian Rukamp

Zhao-Zhao Li

Steven W Oweida

Thomas A Lancaster

A novel class of peptide &#x3b1;-ketoamides useful for selectively inhibiting calpains, selectively inhibiting cysteine proteases, and generally inhibiting all cysteine proteases, having the formula M-AA-AA-CO&#x2014;NH&#x2014;(CH)&#x2014;R. Processes for the synthesis of peptidyl &#x3b1;-ketoamide derivatives. Compositions and methods for inhibiting cysteine proteases, inhibiting calpains, and treating disease caused by cysteine proteases and calpains are provided.

Heterocyclic peptide ketoamides

Methods for treatment and/or prevention of nerve degeneration in mammals using aza-peptide epoxide caspase inhibitors are provided. Aspects of the present disclosure include aza-peptide epoxide compositions to treat or prevent diseases, for example stroke, Alzheimer's disease, Parkinson's disease, multiple sclerosis, neuropathies, Huntington's disease, dentatorubropallidoluysian atrophy, spinocerebellar atrophies, spinal bulbar muscular atrophy, diabetes, amyotrophic lateral sclerosis and other motor neuron diseases. The disclosed methods can be used in combination with calpain inhibitors to treat disease or pathological conditions related to the activity of caspases and calpain associated with a specific disease or condition. Such treatable conditions include stroke, Alzheimer's disease, Parkinson's disease, multiple sclerosis, neuropathies, Huntington's disease, dentatorubropallidoluysian atrophy, spinocerebellar atrophies, spinal bulbar muscular atrophy, nerve degeneration associated with diabetes, amyotrophic lateral sclerosis and other motor neuron diseases, nerve degeneration secondary to primary demyelinating disorders, among others.

Aza-peptide epoxides

The present disclosure provides compositions for inhibiting proteases, methods for synthesizing the compositions, and methods of using the disclosed protease inhibitors. Aspects of the disclosure include peptidyl allyl sulfone compositions that inhibit proteases, for example cysteine proteases, either in vivo or in vitro.

Peptidyl allyl sulfones

The present disclosure provides compositions for inhibiting proteases, methods for synthesizing the compositions, and methods of using the disclosed protease inhibitors. Aspects of the disclosure include a peptidyl propenoyl hydrazide compositions that inhibit proteases, for example cysteine proteases, either in vivo or in vitro.

Propenoyl hydrazides

Compositions and methods for treating neural pathologies are provided. In particular, compositions and methods for treating neural pathologies including axonal degeneration are provided. The compositions include peptide &#x3b1;-ketomides optionally in combination with a second therapeutic agent. Another aspect of the invention provides compositions and methods for treating hyperproliferative disorders. Exemplary compositions for treating hyperproliferative disorders include an anti-proliferative agent such as paclitaxel, in combination with a calpain inhibitor such as AK295.

Ketoamide inhibitors in chronic nerve disease

The present invention provides compositions for inhibiting proteases, methods for synthesizing the compositions, and methods of using the disclosed protease inhibitors. Aspects of the invention include aza-peptide epoxide compositions that inhibit proteases, for example cysteine proteases, either in vivo or in vitro. The disclosed compounds, pharmaceutically acceptable salts, pharmaceutically acceptable derivatives, prodrugs, or combinations thereof can be used to treat disease or pathological conditions related to the activity of proteases associated with a specific disease or condition. Such treatable conditions include viral infections, stroke, neurodegenerative disease, and inflammatory disease, among others.

Tripeptide &agr;-ketoamides

Peptidyl derivatives of diesters of .alpha.-aminoalkylphosphonic acids with basic substituents, their use in inhibiting serine proteases with trypsin-like specificity and their roles as anti-inflammatory agents, anticoagulants, and anti-tumor agents.

Basic .alpha.-aminoalkylphosphonate derivatives

Fluorescent 1-peptidylaminoalkanephosphonate derivatives, and their use in detecting and studying the distribution of serine proteases in cells and biological systems.

Fluorescent 1-peptidylaminoalkanephosphonate derivatives

A novel class of tetrapeptide .alpha.-ketoamides useful for selectively inhibiting serine proteases, selectively inhibiting cysteine proteases, generally inhibiting all serine proteases, and generally inhibiting all cysteine proteases, having the formula M.sub.1 --AA.sup.1 --AA.sup.2 --AA.sup.3 --AA.sup.4 --CO--NR.sub.3 R.sub.4.

Tetrapeptide .alpha.-ketoamides

Novel quaternary pyridinium compounds useful in inhibiting acetylcholinesterase in mammals of the general structure: ##STR1## or pharmaceutically acceptable salts thereof, where R.sub.5 is pentafluorophenyl, phenyl monosubstituted with K, phenyl disubstituted with K, phenyl trisubstituted with K, or naphthyl; R.sub.6 is H, C.sub.1-6 alkyl, phenyl, pentafluorophenyl, phenyl mono, di, or trisubstituted with K, C.sub.1-6 alkyl with an attached phenyl group, C.sub.1-6 alkyl with an attached phenyl group mono, di, or trisubstituted with K; K is halogen, COOH, OH, CN, NO.sub.2, NH.sub.2, C.sub.1-6 alkyl, C.sub.1-6 fluorinated alkyl, C.sub.1-6 alkoxy, C.sub.1-6 alkylamine, C.sub.1-6 alkyl--O--CO--, C.sub.1-6 alkyl--CO--NH--, C.sub.1-6 alkyl--NH--CO--NH--, C.sub.1-6 alkyl--NH--CO--O--, C.sub.1-6 alkyl--NH--CO--, or (C.sub.1-6 alkyl).sub.2 N--CO--; X is OH, C.sub.1-6 alkyl--NH--CO--O--, (C.sub.1-6 alkyl).sub.2 --N--CO--O--, C.sub.1-6 fluoroalkyl--NH--CO--, or (C.sub.1-6 fluoroalkyl).sub.2 --NH--CO--O--; and B is H or C.sub.1-6 alkyl.

Pyridinium compounds

Methods for using novel quaternary pyridinium compounds in inhibiting acetylcholinesterase in mammals, specifically using the quaternary pyridinium compounds in the prophylaxis and treatment of organophosphate poisoning and mammalian dementia by mimicking or opposing the actions of the natural neurotransmitter acetylcholine.

Peptidyl derivatives of diesters of .alpha.-aminoalkylphosphonic acids with basic substitutents, their use in inhibiting serine proteases with trypsin-like specificity and their roles as anti-inflammatory agents, anticoagulants, and anti-tumor agents.

A novel class of peptide .alpha.-ketoamides useful for selectively inhibiting serine proteases, selectively inhibiting cysteine proteases, generally inhibiting all serine proteases, and generally inhibiting all cysteine proteases, having the formula M.sub.1 --AA--NH--CHR.sub.2 --CO--CO--NR.sub.3 R.sub.4, M.sub.1 --AA.sub.2 --AA.sub.1 --CO--NR.sub.3 R.sub.4, M.sub.1 --AA--AA--AA--CO--NR.sub.3 R.sub.4, M.sub.1 --AA--AA--AA--AA--CO--NR.sub.3 R.sub.4, or M.sub.1 --AA--CO--NR.sub.3 R.sub.4.

Peptide ketoamides

Growing community of inventors

Atlanta, GA, United States of America

James C Powers