Med-Chemist : "Quintessential Medicinal Chemistry"
Tuesday, September 24, 2013
Friday, September 20, 2013
Cell death protein could offer new anti-inflammatory drug target
Scientists in Melbourne, Australia, have
revealed the structure of a protein that is essential for triggering a form of
programmed cell death called necroptosis, making possible the development of
new drugs to treat chronic inflammatory diseases such as Crohn's disease and
rheumatoid arthritis.
Thursday, September 19, 2013
Drug blocks light sensors in eye that may trigger migraine attacks
Panda and his collaborators turned to the Lundbeck library of diverse compounds. In hundreds of 384-well plates, a team led by Ken Jones at Lundbeck tested whether each chemical from the library turned off melanopsin by measuring the calcium levels after the plate was exposed to light. When melanopsin is functioning, calcium levels increase after light exposure indicating that light has been sensed and a signal is being generated. Several compounds from the chemical library stopped this calcium increase from happening, suggesting that they were blocking the function of melanopsin.
None of these compounds looked like retinoids, so it was an exciting breakthrough, Panda says. The chemicals, dubbed opsinamides (see structures a few), also
showed no interaction with rhodopsin or other opsins. "We wanted to make sure they were specific to melanopsin," says Panda. To find out whether the opsinamides would have a physiological response in addition to binding to melanopsin in bench experiments, Megumi Hatori and Ludovic Mure from Panda's Salk lab group next looked at whether the drug affected the pupillary constriction in mice. Normally, in extremely bright light, the pupil of the eye shrinks to its smallest size. But when the mice were treated with one of the opsinamides, their pupils didn't shrink as usual. Most importantly, the drug had no detectable effect in mice lacking melanopsin, further showing its specificity for melanopsin. Finally, newborn mice treated with the compound no longer avoided bright lights. The results, Panda says, show that the drug is stopping melanopsin from signaling the brain when the eyes are exposed to bright light.
"So far, everything known about melanopsin has been discovered using knock-out mice that completely lack the receptor," says Panda. "So this offers a new way to study the protein." Kenneth Jones, the former project head at Lundbeck, notes that "the two compounds require further optimization in anticipation of clinical testing but are extraordinarily useful for research purposes and as leads in the discovery process." Co-author Jeffrey Sprouse has co-founded a start-up company, Cyanaptic, to do just that...
Wednesday, September 18, 2013
Investigational oral regimen for hepatitis C shows promise
In a study of an all-oral drug regimen, a majority of volunteers with liver damage due to hepatitis C virus (HCV) infection were cured following a six-month course of therapy that combined an experimental drug, sofosbuvir, with the licensed antiviral drug ribavirin. The results showed that the regimen was highly effective in clearing the virus and well tolerated in a group of patients who historically have had unfavorable prognoses.
Tuesday, September 17, 2013
Promising chronic pain drug developed
4a,9-dihydroxy-7a-(hydroxymethyl)-3-methyl-2,3,4,4a,5,6-hexahydro-1H-4,12-methanol benzofuro[3,2-e]isoquinoline-7(7aH)-one (UMB 425)
Spotlighted in a recent issue of ACS Chemical Neuroscience, the compound, known as UMB 425, is as strong as morphine, but displays diminished tolerance over time with no obvious toxic effects.
"UMB 425 is a breakthrough in the development of therapeutics to treat chronic pain," says Coop. "Unlike other drugs developed to act on only one biological target, UMB 425 acts on two different opioid receptors in the body. When activated at the same time, these receptors work together to provide pain relief and slow the body's development of tolerance to the drug. This diminished tolerance allows a lower dose of the opioid to be administered for a longer time period, while still achieving the same level of pain relief."
For individuals living with chronic pain, either as a result of injury or disease such as arthritis, opioids are the standard treatment. But as the dosage increases to offset the body's tolerance to their effects, opioids cause a number of adverse effects, including constipation, nausea, drowsiness, and dizziness. The unique dual-profile of UMB 425 -- made possible through Coop's collaborations with Alexander MacKerell, PhD, professor in PSC and director of the School's Computer Aided Drug Design Center, and Maureen Kane, PhD, assistant professor in PSC and co-director of the School's Mass Spectrometry Facility -- provides both pain relief as well as diminished tolerance in one drug.
"Historically, medicinal chemists have developed drugs aimed at only one biological target," says Coop. "However, two drugs administered together have the potential to metabolize differently in different individuals, as well as affect patients' adherence to both drugs. A single compound that is able to provide both pain relief and diminished tolerance has the advantage of a defined ratio that we can optimize to ensure patients receive the maximum pain relief, while experiencing minimum adverse effects."
Monday, September 16, 2013
Eating whole fruits linked to lower risk of Type 2 diabetes
Eating more whole fruits, particularly blueberries, grapes, and apples, was significantly associated with a lower risk of type 2 diabetes, according to a new study led by Harvard School of Public Health (HSPH) researchers. Greater consumption of fruit juices was associated with a higher risk of type 2 diabetes. The study is the first to look at the effects of individual fruits on diabetes risk.
Friday, September 13, 2013
Unexpected use of former cancer drug, Zebularine...
Researchers at Lund University have unexpectedly discovered that an old cancer drug can be used to prevent rejection of transplanted tissue. The researchers now have high hopes that their discovery could lead to new treatments for both transplant patients and patients with autoimmune diseases.
"Our group were studying the effects of the old tumour drug Zebularine, (see structure) developed in the USA in the 1960s, and by chance we discovered that it had completely unexpected effects on the immune system," says Leif Salford, Senior Professor of Neurosurgery.
"It turned out that Zebularine has the ability to subdue the reaction of the body's immune system. This could be important in situations where tissue or organs are transplanted. We also think it could be used to curb the body's attacks on its own tissue in autoimmune diseases, for instance type 1 diabetes or rheumatoid arthritis," says Dr Nittby.
In studies on animals, the researchers used rats that were made diabetic. The researchers transplanted the islets of Langerhans cell groups in the pancreas producing insulin -- from healthy rats from another kind of rat into those with diabetes. The diabetic rats were divided into two groups; one group were treated with Zebularine and the other, the control group, did not receive any treatment. The diabetic rats that were treated with Zebularine survived for a significantly longer period than the untreated rats.
"It is very interesting that we only treated them with Zebularine for two weeks, but the effects of the treatment could be observed throughout the 90-day follow-up period.
"The findings are very exciting and are a sign that the immune system was not just generally suppressed, but that the treatment was more targeted. Neither did we see any signs of side-effects," said Dr Nittby.
The researchers are now working intensively to further refine the treatment. The next step is to teach certain cells in the immune system -- the dendritic cells -- to accept certain specific proteins using the Zebularine treatment. This would mean that the treatment could be targeted even more.
Thursday, September 12, 2013
Drug reduces hospitalizations and cost of treating young children with sickle cell anemia
The study is the largest ever focusing on the economic impact of the drug hydroxyurea (see structure below)
in children with the inherited blood disorder. The result supports expanded use of the drug to extend the length and quality of life for sickle cell anemia patients of all ages, said Winfred Wang, M.D., a member of the St. Jude Department of Hematology and principal investigator of the multicenter federally funded trial known as BABY HUG.
"We estimate that hydroxyurea cut overall annual medical expenses about $3,000 for each patient by helping patients avoid disease complications that require inpatient hospital care," said Wang, who is first and corresponding author of the Pediatrics study. "We expect those savings will grow along with patients, whose symptoms often increase in severity and frequency as they age."
About 100,000 individuals in the U.S. and millions worldwide have sickle cell disease, which leaves them at risk for premature death and disability. The disease is the most common genetic disorder affecting African-American individuals, but those from other ethnic and racial backgrounds also inherit mutations in the hemoglobin gene. The mutations result in blood cells that are prone to assuming the sickled shape that gives the disease its name and that leave patients at increased risk for episodes of acute pain, stroke, organ damage and other complications.
Tuesday, September 10, 2013
Scientists fish for new epilepsy model and reel in potential drug
According to new research on epilepsy, zebrafish have certainly earned their stripes. Results of a study in Nature Communications suggest that zebrafish carrying a specific mutation may help researchers discover treatments for Dravet syndrome (DS), a severe form of pediatric epilepsy that results in drug-resistant seizures and developmental delays.
Scientists fish for new epilepsy model and reel in potential drug
Monday, September 9, 2013
Synthetic polymer could stop the spread of HIV
The researchers created the large molecule with several sugar molecules, known as glycopolymers (Glycopolymer is synthetic polymer with pendant carbohydrates). By using different sugars attached to the macromolecule in solution, the scientists were able to investigate which sugar molecules were the most effective in inhibiting the potential binding of the virus.
They then measured how the designed macromolecules compete with the virus to bind to the dendritic cells of the immune system at different concentrations.
"These are preliminary but encouraging results for potentially preventing the spread of the HIV by sexual contact," said Dr Remzi Becer from Queen Mary's School of Engineering and Materials Science.
"We've shown that our synthetic molecule binds to the immune cell, which in turn blocks the virus from attaching and entering. The precisely designed macromolecules could be an ingredient of a condom cream or vaginal gel to act as a physical barrier from allowing the virus into the body."
Dr Becer added: "While this isn't a cure for HIV, it is a novel approach that could dramatically slow down the spread of HIV by sexual contact, and a model that could be replicated to treat other sexually transmitted diseases."
Saturday, September 7, 2013
Alzheimer's 'missing link' found: Promising target for new drugs
Yale School of Medicine researchers have discovered a protein that is the missing link in the complicated chain of events that lead to Alzheimer's disease, they report in the Sept. 4 issue of the journal Neuron. Researchers also found that blocking the protein with an existing drug can restore memory in mice with brain damage that mimics the disease.
Friday, September 6, 2013
Thursday, September 5, 2013
FDA Advisory Committee Unanimously Recommends Approval Of Bayer's Riociguat In Two Pulmonary Hypertension Indications
We know that, Riociguat is (BAY 63-2521) is a novel drug that is in clinical development by Bayer. It is a stimulator ofsoluble guanylate cyclase (sGC). At the moment Phase III clinical trials investigate the use of riociguat as a new approach to treat two forms of pulmonary hypertension (PH): chronic thromboembolic pulmonary hypertension (CTEPH) and pulmonary arterial hypertension (PAH). Riociguat constitutes the first drug of a novel class of sGC stimulators.
Monday, September 2, 2013
Drug used for blood cancers may stop spread of breast cancer cells
In continuation of my update on Decitabine
A drug used to treat blood cancers may also stop the spread of invasive breast cancer, researchers at Mayo Clinic in Florida have discovered. Their study, published online in Breast Cancer Research, found that in the lab and in animals, the drug decitabine turns on a gene coding for protein kinase D1 (PRKD1) that halts the ability of cancer cells to separate from a tumor and spread to distant organs.
Friday, August 30, 2013
Study: Type 2 diabetic patients treated with DPP-4 linagliptin experience reductions in blood glucose levels
Data published in The Lancet showed that elderly people with Type 2 Diabetes (T2D) treated for 24 weeks with the dipeptidyl peptidase-4 (DPP-4) inhibitor linagliptin, marketed by Boehringer Ingelheim and Eli Lilly and Company, experienced significant reductions in blood glucose levels (HbA1c) compared with those receiving placebo. In addition, the overall safety and tolerability profile of linagliptin was similar to placebo, with no significant difference in hypoglycaemia.
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