MALVERN, PA, United States

Shifa Biomedical Corporation

www.shifabiomedical.com
MALVERN, PA, United States

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Endothelial Lipase (EL) inhibitors and methods of using such inhibitors for treating conditions implicating EL are provided herein. The present invention meets the needs in the field by providing small molecule inhibitors of EL function that can be used therapeutically to raise HDLcholesterol levels in blood, and can be used in the prevention and/or treatment of cholesterol and lipoprotein metabolism disorders, including, but not limited to, familial hypercholesterolemia, atherogenic dyslipidemia, atherosclerosis, and, more generally, cardiovascular disease (CVD).


Patent
Temple University and Shifa Biomedical Corporation | Date: 2014-10-06

The present invention relates to pharmaceutical compositions comprising furan-2-sulfonamide derivatives. The present invention further relates to methods of treatment of diseases or conditions associated with endothelial lipase activity, including coronary artery disease and low HDL-C.


Disclosed are compounds that modulate the physiological action of the proprotein convertase subtilisin kexin type 9 (PCSK9), as well as therapeutic methods for use of such compounds to reduce LDL-cholesterol levels and/or for the treatment and/or prevention of cardiovascular disease (CVD), including treatment of hypercholesterolemia. Examples of compounds include thiadiazole, isoxazole, 1,2,4-triazole, thiazole, indole, pyrazole, and pyrrolinone derivatives.


Patent
Shifa Biomedical Corporation | Date: 2014-03-04

Compositions and methods for synthesizing virus-like particles (VLPs) and methods of use thereof are provided.


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase II | Award Amount: 1.34M | Year: 2010

DESCRIPTION (provided by applicant): Heart disease is the leading cause of death for both men and women in the US, accounting for nearly 40% of all annual deaths. A high cholesterol level is well-known risk factors for heart disease. Although blood cholesterol can be lowered using a number of marketed drugs, of which statins are the leading drugs, only 38% of patients taking these drugs are achieving the low-density lipoprotein cholesterol goals set by the National Cholesterol Education Program (NCEP). Furthermore, patients with homozygous familial hypercholesterolemia who have markedly elevated cholesterol levels respond poorly to current drug therapy, and are at very high risk of premature cardiovascular disease. These and other patients will dramatically benefit from an aggressive treatment of hypercholesterolemia. The long-term goal of this work is to develop novel drugs for cholesterol lowering. Our therapeutic target is the protease proprotein convertase subtilisin-like kexin type 9 (PCSK9). PCSK9 controls the degradation of the LDL receptor (LDLR) in the liver and thereby contributes to cholesterol homeostasis. PCSK9 is synthesized as a precursor protein that undergoes processing between the prodomain and catalytic domain. This processing is required for PCSK9 to be secreted and to undertake its biological activity. Our goal is to identify compounds that prevent the processing of PCSK9, thus prevent its secretion and its ability to participate in the degradation of the LDL receptor. To achieve our Phase I goal, we have integrated virtual (computer) screening methods with cell-based assays and consequently identified five screening hits. As part of this Phase II proposal, we plan to expand and optimize our hits, and confirm the ability of selected compounds to stabilize the LDLR and decrease the LDL-C level using in situ and in vivo studies. PUBLIC HEALTH RELEVANCE: Heart disease is the leading cause of death for both men and women in the US. A high cholesterol level is a well-known risk factor for heart disease. Although blood cholesterol can be lowered using a number of marketed drugs, these drugs do not treat a segment of the population with very high cholesterol. Our goal is to develop new cholesterol lowering drugs that have an effect on all individuals with high cholesterol levels, including that segment of the population having very high cholesterol levels.


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 296.73K | Year: 2012

DESCRIPTION (provided by applicant): Influenza and other infectious diseases are a major cause of death in the US and world-wide. Vaccination is the most cost-effective strategy to prevent these diseases. Although much progress has been made in vaccine technology, the timely design, validation and production of vaccines remains a major hurdle for the vaccine industry. The development of recombinant methods for the expression of subunit vaccines has impacted development timelines and costs but subunit vaccines frequently are not as potent as virus particles in eliciting an immune response. Virus like particles or VLPs represent one approach to bridge this potency gap but the design, expression and purification of VLPs remains problematic and the development of uniform tools to aid in vaccine production is elusive with existing technologies. In this proposal we describe a novel cassette technology of integrating recombinant proteins into the structure of VLPs. The prototype system defined in this proposal willgenerate VLPs using the influenza hemagglutinin as an immunogen. The potency of the VLP vaccine will be tested in animals in comparison to a monomeric hemagglutinin. PUBLIC HEALTH RELEVANCE: The influenza virus is highly infectious and causes bothseasonal and pandemic outbreaks. A pandemic outbreak of a highly lethal strain would cause millions of deaths worldwide. Vaccines are the most cost- effective strategy to prevent infection. New strategies are required to produce more effective vaccines and to expedite the development time for new vaccines. Our goal is to develop a novel technology for the design and development of virus like particles that can be used in vaccines.


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase II | Award Amount: 1.54M | Year: 2012

Project Summary/Abstract Cardiovascular disease remains the leading cause of morbidity and mortality for both men and women, accounting for nearly 40% of annual deaths. High levels of LDL-C and low levels of HDL-C are well-known risk factors for heart disease. Although lowering low-density lipoprotein cholesterol (LDL-C) levels using a number of marketed drugs, of which statins are the leading drugs, has significantly reduced coronary artery disease, substantial residual cardiovascular risk remains, even with very aggressive reductions in levels of LDL-C. Accordingly, attention is now shifting toward strategies for targeting HDL-C as adjunctive therapy to prevent and treat cardiovascular disease. Many studies have emphasized that the risk factor associatedwith low levels of HDL-C is independent of that of high LDL-C. Recent epidemiological data confirmed that patients with low HDL-C level are at high risk of premature cardiovascular disease no matter how low the LDL-C level. These and other patients will dramatically benefit from an aggressive treatment of low HDL-C. The long-term goal of the proposed studies is to develop novel drugs for increasing HDL-C. Our therapeutic target is endothelial lipase (EL), a member of the lipoprotein lipase gene family thathydrolyzes HDL-C phospholipids. Recent studies demonstrated that inhibition of EL in mice results in a significant increase in HDL-C levels. In Phase I, we have identified selective inhibitors of EL and developed preliminary SAR. As part of this Phase II proposal, we plan to expand and optimize our hits, and confirm the ability of selected compounds to increase the HDL-C level using in vivo animal models.


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 347.22K | Year: 2012

Project Summary/Abstract Thrombosis is a primary cause of death in the US and developed world. Fatal or debilitating blood clots occur in the three major diseases of the western world: heart attacks, stroke and cancer. Two of the major drugs used therapeutically to prevent blood clots are in the top drugs causing serious adverse effects, particularly bleeding, leading to emergency room treatment of patients. Our goal is to develop new antithrombotic drugs that overcome the limitations of current marketed drugs. Our molecular target is the prothrombinase complex. To that end, we will integrate virtual (computer) screening methods and biophysical/biochemical assays to identify lead compounds that can potentially be optimized to produce novel drugs for the treatment of thrombosis. Virtual screening, which requires the availability of atomic resolution 3D structures of the target protein, provides a cost effective way to screen millions of compounds to identify just a few to be purchased and tested in a biological or biochemical assay. Our access to such 3D structures of Factor Xa makes this work possible. The specific aims of this work are to: 1. Use virtual screening methods to identify compounds that bind in the FXa-Va interface. 2. Determine the binding of compounds selected in Specific Aim 1 to FXa using biophysical assays. 3. Determine inhibitory activity of the selected compounds confirmed in Specific Aim 2 using in vitro assay systems.


Disclosed are compounds that modulate the physiological action of the proprotein convertase subtilisin kexin type 9 (PCSK9), and methods of using these modulators to reduce LDL-cholesterol levels and/or for the treatment and/or prevention of cardiovascular disease (CVD), including treatment of hypercholesterolemia.


Disclosed are compounds that modulate the physiological action of the proprotein convertase subtilisin kexin type 9 (PCSK9), as well as therapeutic methods for use of such compounds to reduce LDL-cholesterol levels and/or for the treatment and/or prevention of cardiovascular disease (CVD), including treatment of hypercholesterolemia. Examples of compounds include thiadiazole, isoxazole, 1,2,4-triazole, thiazole, indole, pyrazole, and pyrrolinone derivatives.

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