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MENLO PARK, CA, United States

Stategics, Inc. | Date: 2010-08-10

The invention relates to compounds and their use in the treatment of thrombocytopenia resulting from diseases or conditions such as immune thrombocytopenic purpura, cancer chemotherapy, surgery, bone marrow or stem cell transplantation, radiation injury or treatment, chronic viral infection, and pancytopenia. The invention further relates to pharmaceutical compositions containing the compounds and compositions of the invention as well as methods for treating such diseases or conditions in a mammal, including a human, by administering to such mammal an effective amount of a selected thrombopoietin receptor agonist.

Disclosed herein are erythropoietin-mimetic compounds of Formula I, which modulate the survival, function, or differentiation of, for example, kidney cells, neurons, erythroid cells, or other erythropoietin-responsive cells. The present invention also relates to compounds and methods that preferentially modulate cells expressing the tissue-protective erythropoietin receptor. The compounds of the invention are useful in preventing and treating diseases, such as anemia, organ injury, and diseases of the central nervous system, and as an adjunct to cellular treatments, such as stem cell therapies.

Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 187.65K | Year: 2008

DESCRIPTION (provided by applicant): The discovery of the expression of erythropoietin receptor (EPOR) in the central nervous system (CNS) has led to a surge in research related to neuroprotection by erythropoietin (EPO), in addition to its well-known hema topoietic properties. EPO induces neuroprotective effects in the CNS through, for example, inhibition of apoptosis in neurons and cerebrovasculature, and it also improves tissue oxygenation through the promotion of angiogenesis and induction of erythroid c ell differentiation. Treatment with recombinant human (rh) EPO was also associated with an improvement in follow-up and outcome scales and a strong trend for reduction in infarct size in patients with ischemic stroke. However, rhEPO has only limited abilit y to cross the blood-brain barrier (BBB), and therefore, the concentrations of rhEPO in the central nervous system are far lower than in circulation. Low molecular weight EPO mimetics were recently described with in vitro neuroprotective and in vivo hemato poietic activities, but improvements in potency, pharmacokinetics, and drug properties for CNS activity are required for optimal in vivo efficacy for neuroprotection. The objective of this research program is to identify additional small molecule EPO mimet ic compounds and to perform initial analysis of structure-activity relationships. Moreover, this program aims to analyze these compounds for their neuroprotective activities and pharmacokinetics for CNS penetrance. The overall goal is to one day develop th ese compounds for ischemic stroke, because rhEPO has demonstrated clinical proof-of-concept in this indication, and the improved physical and functional properties of the proposed low molecular weight EPO mimetics would provide significant benefits for the se patients when compared to treatment with rhEPO. Novel EPO mimetics from this approach are expected to demonstrate improved BBB permeability, while at the same time providing the convenience and safety of once-daily oral dosing and a lack of immunogenici ty, a risk associated with rhEPO. Stroke represents a major unmet medical need and the economic burden of stroke in the United States alone has been estimated in the trillions of dollars. PUBLIC HEALTH RELEVANCE: The objective of the proposed studies is to identify and characterize drug-like low molecular weight erythropoietin mimetics to provide candidate new therapies for ischemic stroke. The compounds derived from the proposed studies have the potential to improve the therapeutic approaches in stroke pat ients, as well as in other diseases of the central nervous system when neuroprotective effects are desired.

Stategics, Inc. | Entity website

STATegics, Inc., all rights reserved

Stategics, Inc. | Entity website

STATegics product pipeline is focused on allosteric small molecule modulators of clinically and commercially relevant cytokine receptors. STATegics small molecules, Allomimetics, offer unique competitive advantages when compared to recombinant proteins or antibodies particularly when bioavailability in tissues or the central nervous system (CNS) is required ...

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