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News Article | December 27, 2016
Site: www.eurekalert.org

Vanderbilt University scientists have received notification from the U.S. Food and Drug Administration (FDA) that testing in humans may proceed for an investigational new drug for Alzheimer's disease after more than 10 years of research by scientists at Vanderbilt University and Vanderbilt University Medical Center. It is relatively uncharted territory for an academic drug discovery group to take a molecule from the laboratory setting to the clinical trials stage. "The movement to the clinical phase of the research is the result of tireless colleagues reaching across disciplines in pursuit of the shared goal of hoping to someday improve the lives of individuals with Alzheimer's disease and possibly other brain disorders, such as schizophrenia," said Provost and Vice Chancellor for Academic Affairs Susan R. Wente, Ph.D. "This work exactly illustrates the critical role that basic science conducted in partnership with a world-class medical center can play in advancing knowledge in an attempt to fight a devastating disease." For Alzheimer's disease, the aim is for the investigational drug to target major pathologies of the disease and selectively activate a key receptor in the brain. The Vanderbilt researchers believe that the current standard of care for Alzheimer's disease, cholinesterase inhibitors, has a different mechanism of action. They are hoping to establish through future clinical testing that the molecule is broadly effective across a number of cognitive and neuropsychiatric disorders, including schizophrenia. "This is the first instance I am aware of where an academic drug discovery group moved a molecule designed to hopefully treat a chronic brain disorder all the way from early discovery to human trials without there being, at some point along the way, a pharmaceutical partner," said P. Jeffrey Conn, Ph.D., Lee E. Limbird Professor of Pharmacology in the Vanderbilt University School of Medicine and director of the Vanderbilt Center for Neuroscience Drug Discovery (VCNDD). "And that really is crossing what people refer to all of the time as the 'Valley of Death,' where good research discoveries have a hard time moving into the clinical testing phase due to lack of funding," he said. "Importantly, at this early stage, the FDA has only granted permission to assess potential safety of this investigational new drug in healthy volunteers" said Conn. "We cannot predict the outcome, but if these studies are successful in demonstrating that the investigational drug can be safely administered to humans, this would pave the way to allow filing of additional applications with the FDA to seek permission to advance to testing for efficacy in improving cognitive function in patients suffering from Alzheimer's disease, and possibly schizophrenia or other brain disorders. While we cannot predict the outcome of any future safety or efficacy studies, this decision by FDA allowing clinical research to begin represents a major milestone in allowing us to hopefully provide answers to those critical questions in the future." VCNDD Co-Director Craig W. Lindsley, Ph.D., director of Medicinal Chemistry and William K. Warren, Jr. Professor of Medicine, said Phase I testing will assess drug safety and tolerability in healthy volunteer participants, a process that could take a year. If successful, the Phase II and III studies would include efficacy assessments in patients with Alzheimer's disease and could take three to five years to complete. "We are hoping to address what we see as an unmet medical need," Lindsley said. "For Alzheimer's patients, the standard of care for symptomatic treatment remains cholinesterase inhibitors, which are 25 years old at this point. There hasn't been any real scientific advancement in this field in a long time." Lindsley and Conn credit The William K. Warren Foundation for its philanthropic investments along the way to make clinical trials for this investigational drug a reality. "One of the most challenging things about doing this in an academic environment is funding," Lindsley said. "Every step requires funding and if there is a delay or break in funding, then everything sits idle and potentially innovative approaches for patient care do not advance." "Being matched with the Warrens happened serendipitously. They have invested so much in our programs, and it is wonderful to show them progress on their investments," he said. "Without the financial support from the Warrens, this investigational drug would not be poised to enter human clinical trials." The William K. Warren Foundation Chief Executive Officer John-Kelly Warren said he is gratified that FDA has allowed for the investigational drug to proceed to testing in human beings. "Although this is an important sequential milestone, the only milestone that matters to us is the hope that one day we will learn that this investigational new drug has positively and safely changed the life of a patient suffering from a brain disorder such as schizophrenia or Alzheimer's disease," Warren said. "That day will warrant a celebration felt in the heavens. Until then, we are prepared to support the VCNDD research team until they can deliver the necessary results," he said. A NIH National Cooperative Drug Discovery/Development grant funded the early basic science and discovery of this investigational drug and the Alzheimer's Drug Discovery Foundation and Harrington Discovery Institute helped support some of the key toxicity studies that FDA required, Conn said. "The investigational new drug has the potential to improve cognitive functions with fewer unwanted side effects. This could someday be an important advance for the treatment of cognitive deficits in psychiatric disorders and Alzheimer's disease," said Joshua Gordon, M.D., Ph.D., director of the National Institute of Mental Health, which co-funded the research. Conn and Lindsley said Vanderbilt's "team science" approach included contributions from the director of Translational Pharmacology and Development for the VCNDD and Assistant Professor Carrie K. Jones, Ph.D., who coordinated the IND drafting, submission, and subsequent development into Phase I, director of Molecular Pharmacology for the VCNDD and Research Associate Professor of Pharmacology Colleen Niswender, Ph.D., for the molecular pharmacology; Research Assistant Professor of Pharmacology Jerri Rook, Ph.D., for the behavioral studies; and Research Assistant Professor of Pharmacology Thomas Bridges, Ph.D., and Research Assistant Professor of Pharmacology Anna Blobaum, Ph.D., for drug metabolism and pharmacokinetic profiling. Paul Newhouse, M.D., director of the Center for Cognitive Medicine at VUMC and Jim Turner Professor in Cognitive Disorders, is expected to lead the upcoming clinical study funded in part by the Alzheimer's Association and Alzheimer's Drug Discovery Foundation.


News Article | November 28, 2016
Site: cen.acs.org

In a first for an academic drug discovery group, the Vanderbilt Center for Neuroscience Drug Discovery has received FDA approval to put a treatment for brain disorders into the clinic without any help from the pharmaceutical industry. A study assessing the safety of the compound, a positive allosteric modulator of muscarinic acetylcholine receptor 1 (M1) for Alzheimer’s disease and schizophrenia, will begin early next year. Academic drug discovery centers such as VCNDD typically focus on generating early-stage compounds that are spun off into companies or licensed to partners with the cash and experience to push them into clinical studies. Since it was established in 2008, VCNDD has secured several drug discovery partnerships with big pharma firms for preclinical compounds developed in its labs. But with many drug firms exiting neuroscience research, some of those programs have stalled. For example, Bristol-Myers Squibb decided to exit neuroscience R&D a year into a collaboration with VCNDD to develop positive allosteric modulators of mGlur4 for Parkinson’s disease. Another partner, AstraZeneca, shut down its neuroscience unit, and the Vanderbilt team subsequently regained rights to positive allosteric modulators of M4. Big pharma’s waning commitment to neuroscience prompted a shift in strategy at VCNDD. For the past two years, the academic team has focused on putting molecules through early clinical studies in the hope that they will have a better chance of getting to patients. “We rarely see companies license a clinical-stage asset and then back out of it for non-science-based reasons,” notes VCNDD Director P. Jeffrey Conn. “We felt that if we partnered at a later stage, it gives programs a better chance of going the distance.” That shift has meant building up capabilities beyond drug discovery. Although the VCNDD scientists have tapped some consultants, “we did the bulk of the work” necessary to get the drug candidate to the point where it could enter Phase I studies, notes Craig Lindsley, VCNDD’s director of medicinal chemistry. As an academic lab, putting compounds into the clinic without the help of big pharma has also meant “a unique cobbling of money,” Lindsley says. NIH funded much of the basic science on the M1 receptor, and in 2014 the William K. Warren Foundation kicked in $5 million to support the preclinical studies. Those data allowed VCNDD to get grants from the Alzheimer’s Association and Alzheimer’s Drug Discovery Foundation to support the Phase I trials. The M1 modulator addresses cognitive functions—thinking and problem-solving capabilities, for example—as well as negative symptoms such as social withdrawal and irritability, associated with brain disorders.


Visco M.D.,Ohio State University | Wieting J.M.,Ohio State University | Wieting J.M.,Vanderbilt Center for Neuroscience Drug Discovery | Mattson A.E.,Ohio State University
Organic Letters | Year: 2016

Sterically encumbered organosilanes can be difficult to synthesize with conventional, strongly basic reagents; the harsh reaction conditions are often low yielding and not suitable for many functional groups. As an alternative to the typical anionic strategies to construct silanes, the coupling of benzylic halides and arylhalosilanes with sonication has been identified as a high yielding and general strategy to access bulky and functionalized benzylic silanes. This new methodology provides a solution for the synthesis of families of bulky benzylic silanes for study in catalysis and other areas of chemical synthesis. © 2016 American Chemical Society.


Wenthur C.J.,Vanderbilt University | Lindsley C.W.,Vanderbilt University | Lindsley C.W.,Vanderbilt Center for Neuroscience Drug Discovery
ACS Chemical Neuroscience | Year: 2013

Clozapine was the first true breakthrough in schizophrenia treatment since the discovery of chlorpromazine in 1950, effectively treating positive, negative, and some cognitive symptoms, as well as possessing unprecedented efficacy in treatment-resistant patients. Despite over 30 years of intense study, the precise molecular underpinnings that account for clozapine's unique efficacy remain elusive. In this Viewpoint, we will showcase the history and importance of clozapine to neuroscience in general, as well as for the treatment of schizophrenia, and review the synthesis, pharmacology, drug metabolism, and adverse events of clozapine. © 2013 American Chemical Society.


Wenthur C.J.,Vanderbilt University | Bennett M.R.,Vanderbilt University | Lindsley C.W.,Vanderbilt University | Lindsley C.W.,Vanderbilt Center for Neuroscience Drug Discovery
ACS Chemical Neuroscience | Year: 2014

Fluoxetine (Prozac) was the first major breakthrough for the treatment of depression since the introduction of tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs) nearly 30 years earlier. It was the first selective serotonin reuptake inhibitor (SSRI) approved by the United States Food and Drug Administration, offering superior efficacy and reduced side effects relative to TCAs and MAOIs. Though a debate remains regarding the exact mechanism by which the clinical efficacy of fluoxetine is manifested, the importance of fluoxetine and related SSRIs to the field is unquestionable. The trade name Prozac has permeated popular culture, helping to raise awareness of depression and to diminish the prevalence of long-standing stigmas associated with this illness. In this Review, we will showcase the history and importance of fluoxetine to neuroscience in general, as well as for the treatment of depression, and review the synthesis, pharmacology, drug metabolism, and adverse effects of fluoxetine. © 2013 American Chemical Society.


O'Reilly M.C.,Vanderbilt University | Lindsley C.W.,Vanderbilt University | Lindsley C.W.,Vanderbilt Center for Neuroscience Drug Discovery
Tetrahedron Letters | Year: 2012

In this Letter, we describe a novel three-step, one-pot procedure for the enantioselective synthesis of N-benzyl protected morpholines and orthogonally N,N′-protected piperazines with chiral alkyl groups installed at the C2 position of each heterocyclic core via organocatalysis. This methodology allows for the rapid preparation of functionalized morpholines and piperazines that are not readily accessible through any other chemistry in good to excellent % ee (55-98% ee). © 2011 Elsevier Ltd. All rights reserved.


News Article | September 20, 2016
Site: www.biosciencetechnology.com

Researchers at Vanderbilt University Medical Center have discovered a key mechanism that explains how compounds they’re developing can suppress schizophrenia-like symptoms in mice without side effects. On the basis of this discovery, reported this month in the journal Neuron, “we now have much stronger understanding of the therapeutic potential and mechanism of action of compounds that are advancing to clinical development,” said P. Jeffrey Conn, Ph.D., director of the Vanderbilt Center for Neuroscience Drug Discovery. An estimated 3 million Americans have schizophrenia, which is associated with excessive amounts of the neurotransmitter dopamine in a part of the forebrain called the striatum. Current medications reduce hallucinations and delusions, the hallmark of schizophrenia, by blocking dopamine receptors. But because they also block dopamine receptors in the cerebral cortex, they can worsen cognitive difficulties. That’s why a new treatment approach is urgently needed, said Conn, the Lee E. Limbird Professor of Pharmacology at Vanderbilt University School of Medicine. Several years ago, a drug being tested in humans for treatment of Alzheimer’s disease was shown to have “robust” effects in reducing psychotic symptoms in both Alzheimer’s and schizophrenia patients. The drug activated “muscarinic” receptors in the brain that bind the neurotransmitter acetylcholine. While the drug didn’t make it to market, Conn and his colleagues seized on the possibility that activating muscarinic receptors could be a new way to treat schizophrenia. For several years, they have been developing positive allosteric modulators, or PAMs, drug-like compounds that can “tune up” the activity of receptors in specific areas of the brain. They identified a particular muscarinic receptor, M4, and developed compounds — PAMs — that increase its activity. As expected, switching on the M4 “amplifier” in animals produced anti-psychotic-like effects similar to those observed in the clinical trial. A big unanswered question was how M4 activation mediated this antipsychotic activity. The current study showed that the M4 PAMs didn’t block dopamine receptors, but prevented dopamine from being released in the first place. To find out how, Daniel Foster, Ph.D., research instructor in Pharmacology and first author of the paper, used genetically-modified mice in which the gene for the M4 receptor was selectively deleted from different neuron populations. In this way, he traced the primary source of M4 receptors to “spiny projection neurons,” which receive signals from dopamine neurons, but which were not previously known to send signals back. This suggested to the researchers that spiny projection neurons must release a signaling molecule that can affect dopamine release. They looked for compounds released by the neurons and identified an endocannabinoid called 2-arachidonoylglycerol, which binds to the cannabinoid CB2 receptor on dopamine neurons. Endocannabinoids are natural signaling molecules that activate cannabinoid receptors in the brain. While the CB1 receptor is associated with reward and binds THC, the active compound in marijuana, the CB2 receptor previously had been linked primarily to immune function. The Vanderbilt study defines a new role for CB2 — modulating dopamine signaling in the striatum, Conn said. This provides a mechanism by which the M4 PAM can relieve psychotic symptoms without causing adverse cognitive effects in other parts of the brain, he said.


Sheffler D.J.,Vanderbilt Center for Neuroscience Drug Discovery | Pinkerton A.B.,Sanford Burnham Institute for Medical Research | Dahl R.,Sanford Burnham Institute for Medical Research | Markou A.,University of California at San Diego | Cosford N.D.P.,Sanford Burnham Institute for Medical Research
ACS Chemical Neuroscience | Year: 2011

Group II metabotropic glutamate (mGlu) receptors consist of the metabotropic glutamate 2 (mGlu2) and metabotropic glutamate 3 (mGlu3) receptor subtypes which modulate glutamate transmission by second messenger activation to negatively regulate the activity of adenylyl cyclase. Excessive accumulation of glutamate in the perisynaptic extracellular region triggers mGlu2 and mGlu3 receptors to inhibit further release of glutamate. There is growing evidence that the modulation of glutamatergic neurotransmission by small molecule modulators of Group II mGlu receptors has significant potential for the treatment of several neuropsychiatric and neurodegenerative diseases. This review provides an overview of recent progress on the synthesis and pharmacological characterization of positive and negative allosteric modulators of the Group II mGlu receptors. © 2011 American Chemical Society.


Melancon B.J.,Vanderbilt Center for Neuroscience Drug Discovery | Tarr J.C.,Vanderbilt Center for Neuroscience Drug Discovery | Panarese J.D.,Vanderbilt Center for Neuroscience Drug Discovery | Wood M.R.,Vanderbilt Center for Neuroscience Drug Discovery | Lindsley C.W.,Vanderbilt Center for Neuroscience Drug Discovery
Drug Discovery Today | Year: 2013

Allosteric modulation of AMPA, NR2B, mGlu2, mGlu5 and M1, targeting glutamatergic dysfunction, represents a significant area of research for the treatment of schizophrenia. Of these targets, clinical promise has been demonstrated using muscarinic activators for the treatment of Alzheimer's disease (AD) and schizophrenia. These diseases have inspired researchers to determine the effects of modulating cholinergic transmission in the forebrain, which is primarily regulated by one of five subtypes of muscarinic acetylcholine receptor (mAChR), a subfamily of G-protein-coupled receptors (GPCRs). Of these five subtypes, M1 is highly expressed in brain regions responsible for learning, cognition and memory. Xanomeline, an orthosteric muscarinic agonist with modest selectivity, was one of the first compounds that displayed improvements in behavioral disturbances in AD patients and efficacy in schizophrenics. Since these initial clinical results, many scientists, including those in our laboratories, have strived to elucidate the role of M1 with compounds that display improved selectivity for this receptor by targeting allosteric modes of receptor activation. A survey of selected compounds in this area will be presented. © 2013 Elsevier Ltd. All rights reserved.


Lindsley C.W.,Vanderbilt Center for Neuroscience Drug Discovery
Journal of Medicinal Chemistry | Year: 2014

The identification of sites on receptors topographically distinct from the orthosteric sites, so-called allosteric sites, has heralded novel approaches and modes of pharmacology for target modulation. Over the past 20 years, our understanding of allosteric modulation has grown significantly, and numerous advantages, as well as caveats (e.g., flat structure-activity relationships, species differences, "molecular switches"), have been identified. For multiple receptors and proteins, numerous examples have been described where unprecedented levels of selectivity are achieved along with improved physiochemical properties. While not a panacea, these novel approaches represent exciting opportunities for tool compound development to probe the pharmacology and therapeutic potential of discrete molecular targets, as well as new medicines. In this Perspective, in commemoration of the 2013 Philip S. Portoghese Medicinal Chemistry Lectureship (Lindsley, C. W. Adventures in allosteric drug discovery. Presented at the 246th National Meeting of the American Chemical Society, Indianapolis, IN, September 10, 2013; The 2013 Portoghese Lectureship), several vignettes of drug discovery campaigns targeting novel allosteric mechanisms will be recounted, along with lessons learned and guidelines that have emerged for successful lead optimization. © 2014 American Chemical Society.

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