Virginia Commonwealth University

Center for Innovative Technology

Other

Xechem International, Inc.

Allos Therapeutics, Inc.

Gajanan S Joshi

Donald J Abraham

Richmond E Danso-Danquah

Martin K Safo

Ramnarayan Randad

Stephen J Hoffman

Jayashree Panikker

James C Burnett

Sanjeev Kulkarni

Amal Yousseff

Melissa Grella

Michael J Gerber

Ahmed Mehanna

Mona Mahran

Telih Boyiri

Changging Wang

Changquing Wang

Faik N Musayev

Samuel Nokuri

The provides compounds for the treatment of sickle-cell disease. In particular, the invention provides 5-membered heterocyclic anti-sickling agents that are highly effective and non-toxic, and methods for their use. The compounds include analogues and derivatives of naturally occurring occurring 5-hydroxymethyl-2-furfuraldehyde, 5-Ethyl-2-furfuraldehyde, 5-Methyl-2-furfuraldehyde, and 2-furfuraldehyde, and prodrug forms of the compound.

Anti-sickling agents

Compounds for the treatment of sickle-cell disease, and methods for their use are provided. The compounds have a dual mode of action. First, binding of the compounds to hemoglobin increases the oxygen affinity of both normal and sickle hemoglobin. Secondly, binding of these compounds to the N-terminal amino acid of sickle hemoglobin results in destabilization of potential contacts between sickle hemoglobin molecules, preventing polymerization and the formation of fibrous precipitates of the sickle hemoglobin. The compounds are also useful for inducing hypoxia, e.g. to augment cancer treatments.

A family of substituted chiral allosteric effectors of hemoglobin is useful for delivering more oxygen to hypoxic and ischemic tissues by reducing the oxygen affinity of hemoglobin in whole blood.

Substituted chiral allosteric hemoglobin modifiers

Chemical structures have been identified which allosterically modify pyrvate kinase and inhibit enzymatic activity. These compounds can be used as pharmaceuticals in the treatment of a wide variety of diseases and disorders where influencing metabolic processes is beneficial, such as the glycolytic pathway, all pathways which use ATP as an energy source, and all pathways which involve 2,3-diphosphoglycerate related to the delivery of oxygen by modifying hemoglobin's oxygen affinity, treatments of tumor and cancer and Alzheimer's disease (AD).

Allosteric inhibitors of pyruvate kinase

Chemical structures have been identified which allosterically modify pyrvate kinase and either inhibit or activate enzymatic activity. These compounds can be used as pharmaceuticals in the treatment of a wide variety of diseases and disorders where influencing metabolic processes is beneficial, such as the glycolytic pathway, all pathways which use ATP as an energy source, and all pathways which involve 2,3-diphosphoglycerate.

A family of compounds has been found to be useful for right-shifting hemoglobin towards a low oxygen affinity state. The compounds are capable of acting on hemoglobin in whole blood. In addition, the compounds can maintain the oxygen affinity in blood during storage and can restore the oxygen affinity of outdated blood.

Allosteric modifiers of hemoglobin

Allosteric modifiers of hemoglobin useful for decreasing oxygen affinity

Allosteric hemoglobin modifiers to decrease oxygen affinity in blood

Growing community of inventors

Glen Allen, VA, United States of America

Gajanan S Joshi