SBIR-STTR Award

Memantine, an aminoadamantane, is approved to treat moderate-to-severe Alzheimer's disease in the US and in Europe. Memantine selectively inhibits abnormally active N-methyl-D-aspartate-type glutamate receptor (NMDAR) channels, while preserving normal glutamate activity and physiological neuronal function (Lipton, 2006; Lipton, 2007a,b). Pathological NMDA receptor activity is further down-regulated by Snitrosylation of cysteine residues located on the N-terminus or extracellular domain. Taking advantage of these insights, PRI has developed a proprietary series of bifunctional antagonists, called nitromemantines, that not only preferentially bind to the open-channel state but also selectively target NO to a second modulatory site using the memantine pharmacophore as a homing motif (Wang, 2006, Wang et al. patents). Our data suggest that some of these memantine analogs have good potency, while maintaining selectivity for persistently open NMDAR channels. Most importantly, they appear to have greater neuroprotective properties than memantine in both in vitro and in vivo animal models. Recent work from the laboratory of our collaborator and co-inventor, Professor Stuart Lipton (Burnham Institute) demonstrates the unique ability of one of our nitromemantines (YQW-036, 1-amino-3,5-diethyl-7-nitrateadamantane) to rescue/protect synapses perhaps by superior inhibition of pathogenic extrasynaptic NMDARs (Talantova, 2013) This animal POC combined with the demonstrated safety of nitromemantines support the translation of this basic science work into clinical stage evaluation. Hence, our overall goal is to initiate preclinical studies to support submission of an IND for YQW-036. This effort will begin with Phase I pharmacokinetics and safety studies of YQW-036 as a potential development candidate. Successful completion of the Phase I studies will merit submission of a Phase II application to support IND enabling studies that are required prior to human clinical trials. Successful achievement of these milestones will provide a proprietary first-in-class disease-modifying drug for Alzheimer's disease.

Thesaurus Terms:
2-Cyclopentyl-5-(5-Isoquinolylsulfonyl)-6-Nitro-1h-Benzo(D)Imidazole;Abstracting;Achievement;Aging Population;Alzheimer's Disease;Analog;Animal Model;Animals;Base;Basic Science;Binding (Molecular Function);Brain;Canis Familiaris;Clinical;Clinical Trials;Comparative;Cost Effective;Cysteine;Data;Dementia;Development;Disease;Dose;Drug Kinetics;Effective Therapy;Effectiveness;Europe;Evaluation;Extracellular Domain;Fda Approved;Genotoxicity;Glutamate Receptor;Glutamates;Goals;Health;Homing;Human;Human Tissue;Improved;In Vitro;In Vivo;Incidence;Insight;Institutes;Laboratories;Legal Patent;Liver Microsomes;Measurement;Measures;Memantine;Member;Metabolic;Mus;N-Methyl-D-Aspartate Receptors;N-Methylaspartate;Nerve Degeneration;Neurobiology;Neuronal Injury;Neurons;Nitric Oxide;Nitroglycerin;Novel;Pharmaceutical Preparations;Pharmacodynamics;Pharmacologic Substance;Pharmacology;Pharmacophore;Phase;Phase 1 Study;Phase 2 Study;Physiological;Plasma;Pre-Clinical Model;Preclinical Study;Primates;Professor;Property;Rattus;Rodent;Route;Safety;Safety Study;Series;Site;Staging;Synapses;Technology;Therapeutic;Toxic Effect;Toxicology;Translations;Uptake;Work;

Alzheimer’s disease (AD) is a devastating form of dementia with an increasing incidence due to our aging population. While the FDA-approved N-methyl-d-aspartate (NMDA) receptor drug memantine offers some modest beneficial effect, we have developed much improved novel aminoadamantane nitrates (“NitroSynapsins”) that are bifunctional NMDAR antagonists with selectivity for extra-synaptic eNMDARs relative to synaptic NMDARs. Importantly, this series of drugs has the potential to be a disease- modifying intervention for AD because the lead candidate compound (YQW-036) can reverse synaptic loss in preclinical studies in two AD transgenic animal models and dramatically improve neurobehavior on memory testing. Loss of synaptic function is associated with cognitive decline in AD. In fact, the loss of synapses is a better predictor of cognitive loss in AD than plaques or tangles (Terry, 1991; Sheng, 2012). Emerging evidence suggests that oligomers of A?42 release, via stimulation of ?7 nicotinic receptors, excessive amounts of glutamate from astrocytes, which, in turn activates eNMDARs, at least in part responsible for mediating synaptic damage. In AD, stimulation of eNMDARs also increases hyperphosphorylation of Tau, which gives rise to neurofibrillary tangles and whose deposition strongly correlates with progression of AD (Wang, 2013). Additionally, eNMDAR-mediated increases in Tau protein levels, Tau hyperphosphorylation, and caspase-3 activity in response to oligomerized A? presage the loss of synapses (Ittner, 2010; Zempel, 2010; Hyman, 2011; Jin, 2011; Morris, 2011; Sydow, 2011; D’Amelio, 2011; Talantova, 2013). Our lead NitroSynapsin can reverse these deficits, as shown in the Preliminary Studies (Talantova, 2013). Protection of the synapse may be achieved by eNMDAR antagonists sufficiently potent to protect, yet gentle enough to allow normal synaptic transmission and neurobehavioral improvement. Considering the safety profile of memantine over many years of clinical use, and the vastly improved selectivity and efficacy both in vitro and in vivo of NitroSynapsins over memantine, it seems likely that the enhanced activity of our new drugs will translate into better clinical outcomes in humans. In Phase I, we initiated clinical development of YQW-036, carrying out PK and brain uptake studies, metabolic stability studies and initial toxicity studies. Based on the successful outcome of those studies we plan to initiate IND-enabling studies under this Phase II SBIR application. Our two-year goal is to submit an IND to begin the clinical development of the first-in-class member of this novel AD-modifying class of pharmaceuticals. Phase I: 1R43AG047709-01

Public Health Relevance Statement:
Narrative Alzheimer’s disease (AD) is a devastating form of dementia with an increasing incidence due to our aging population. The FDA-approved drug memantine is arguably the best available therapeutic for AD. We have synthesized an improved memantine-like drug (“Nitrosynapsin”) and have demonstrated its effectiveness in vitro and in an animal model of AD. Development of Nitrosynapsin will result in a novel and potentially disease- modifying treatment for AD.

Project Terms:
absorption; aging population; Alzheimer's Disease; Alzheimer's disease model; Ames Assay; Amyloid beta-Protein; Animal Model; Animals; Astrocytes; Attenuated; base; Binding; Binding Proteins; Biological Assay; Biotin; Brain; Canis familiaris; Cardiotoxicity; CASP3 gene; Cell Survival; Cellular Stress Response; Cerebrum; Chemistry; Clinical; clinical development; Clinical Trials; Cyclic GMP; Cysteine; Dementia; Deposition; Development; Disease; Dose; Drug Interactions; Drug Receptors; Effectiveness; Electroencephalography; Ensure; Evaluation; Excretory function; FDA approved; Future; genotoxicity; Glutamates; Goals; Histology; Human; Immunofluorescence Immunologic; Impaired cognition; improved; In Vitro; in vivo; Incidence; induced pluripotent stem cell; Intervention; Lead; Measurement; Mediating; Memantine; member; Memory; Metabolic; Metabolism; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; neurobehavior; neurobehavioral; neurobehavioral test; Neurofibrillary Tangles; neuron loss; neurotoxicity; Nicotinic Receptors; Nitrates; novel; novel therapeutics; Outcome; patch clamp; Pathology; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology and Toxicology; Phase; Phosphotransferases; Plasma Proteins; preclinical development; preclinical study; Preparation; Process; Rattus; receptor; relating to nervous system; Research; research and development; response; Risk; Role; Safety; scale up; Series; Site; Small Business Innovation Research Grant; success; Synapses; synaptic function; Synaptic Transmission; targeted treatment; tau Proteins; Testing; Therapeutic; therapeutic target; Time; Tissues; Toxic effect; Transgenic Animals; Transgenic Mice; Translating; uptake; Validation; Western Blotting; Work