MALVERN, PA, United States

Time filter

Source Type

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: 290.23K | Year: 2010

DESCRIPTION (provided by applicant): The long-term goal of this work is to develop novel drugs for the treatment of metabolic syndrome (MetS). MetS is an assemblage of associated clinical disorders recognized only some 20 years ago to be linked. They include insulin resistance, hypertension, dyslipidemia (i.e. hypertriglyceridemia and low HDL levels), glucose intolerance, and obesity. The incidence of MetS has reached epidemic proportions afflicting ~64 million Americans and significantly increasing the risk of coronary heart disease (CHD), atherosclerosis, diabetes, myocardial infarction, stroke and even death in those afflicted. At this time there are no drugs available for the treatment of MetS per se. Although drugs do exist for the individual components, complications due to drug interactions, side effects, and the sheer number of drugs that are needed, along with the serious consequences of the disease, make the development of a new approach urgent. To address this need, we will adopt a novel approach to the problem, designing antagonists that target the nuclear receptor HNF4a. HNF4a is a transcription factor involved in lipid and glucose homeostasis and the transcriptional regulation of genes involved in energy metabolism, as well as blood pressure homeostasis. Thus, it is involved in regulation of all components of MetS, and a growing body of biological data supports its role in the treatment of the multiple components of MetS. Current drugs that target antagonizing nuclear receptors bind to the ligand-binding site (LBS) where they alter the dynamics and structure of the receptor, resulting in an inability of necessary coactivators to bind to the coactivator-binding site (AF-2) thus interfering with transcription. Rather than focusing solely on the LBS, we will exploit the unusual multiplicity of sites in a single drug target (AF-2 and LBS) to carry out a, two-site, drug discovery strategy that leverages both experimental and theoretical efforts and provides new mechanistic approaches to overcoming MetS. To this end we will integrate in silico induced-fit docking with cell based transcription assays, X-ray crystallography, and molecular dynamics free energy pertubation and replica exchange simulations to find confirmed hits (X-ray and assays) and determine structural design criteria for lead optimization of compounds at these sites. PUBLIC HEALTH RELEVANCE: Metabolic syndrome (MetS) is an assemblage of associated clinical disorders that includes insulin resistance, hypertension, dyslipidemia (i.e. hypertriglyceridemia and low HDL levels), glucose intolerance, and obesity. The incidence of MetS has reached epidemic proportions afflicting ~64 million Americans and significantly increasing the risk of coronary heart disease, atherosclerosis, diabetes, myocardial infarction, stroke and even death in those afflicted. To develop a drug to address this complex disease, we will take a novel approach, designing compounds that target the nuclear receptor HNF4a, which is involved in regulating all components of this syndrome.


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.

Loading Shifa Biomedical Corporation collaborators
Loading Shifa Biomedical Corporation collaborators