Benjamin Blass

Pharmacologic blockade of 12/15-lipoxygenase ameliorates memory deficits, Aβ and tau neuropathology in the triple-transgenic mice.

The 12/15-lipoxygenase (12/15LO) enzyme is widely distributed within the central nervous system. Previous work showed that this protein is upregulated in Alzheimer’s disease (AD), and plays an active role in the development of brain amyloidosis in amyloid beta (Aβ)-precursor protein transgenic mice (Tg2576). In the present paper, we studied the effect of its pharmacologic inhibition on the AD-like phenotype of a mouse model with plaques and tangles, the triple-transgenic mice. Compared with mice receiving placebo, the group treated with PD146176, a specific 12/15LO inhibitor, manifested a significant improvement of their memory deficits. The same animals had a significant reduction in Aβ levels and deposition, which was secondary to a decrease in the β-secretase pathway. In addition, while total tau-soluble levels were unchanged for both groups, PD146176-treated mice had a significant reduction in its phosphorylation state and insoluble fraction, which specifically associated with decrease in stress-activated protein kinase/c-Jun N-terminal kinase activity. In vitro study showed that the effect on tau and Aβ were independent from each other. These data establish a functional role for 12/15LO in the pathogenesis of the full spectrum of the AD-like phenotype and represent the successful completion of the initial step for the preclinical development of 12/15LO inhibitors as novel therapeutic agents for AD.

12/15-Lipoxygenase Inhibition Reverses Cognitive Impairment, Brain Amyloidosis, and Tau Pathology by Stimulating Autophagy in Aged Triple Transgenic Mice

BACKGROUND The 12/15-lipoxygenase (12/15-LO) enzyme is upregulated in the brains of patients with Alzheimers disease (AD), and its expression levels influence the onset of the AD-like phenotype in mouse models. However, whether targeting this pathway after the neuropathology and behavioral impairments have been established remains to be investigated. METHODS Triple transgenic (3xTg) mice received either PD146176-a selective and specific pharmacological inhibitor of 12/15-LO-or placebo starting at 12 months of age for 12 weeks. They were then assessed for the effect of the treatment on neuropathologies and behavioral impairments. RESULTS At the end of the study, mice in the control group showed a worsening of memory and learning abilities, whereas mice receiving PD146176 were undistinguishable from wild-type mice. The same group also had significantly lower amyloid beta levels and deposition, less tau neuropathology, increased synaptic integrity, and autophagy activation. Ex vivo and in vitro genetic and pharmacological studies found that the mechanism involved in these effects was the activation of neuronal autophagy. CONCLUSIONS Our findings provide new insights into the disease-modifying action of 12/15-LO pharmacological inhibition and establish it as a viable therapeutic approach for patients with AD.

Apelin receptor: its responsiveness to stretch mechanisms and its potential for cardiovascular therapy

It has recently been demonstrated that the apelin receptor (APJ) plays a significant role in mediating the stretch response within the heart in a G-protein-independent and β-arrestin-dependent fashion. This discovery adds to the consolidated literature describing the potential benefits of APJ agonists. In this review, the authors will examine the functional selectivity of APJ and stretch with respect to their ability to signal via both G-protein-dependent and G-protein-independent mechanisms, with a focus on the multifunctional protein, β-arrestin. The possibility of selecting or designing novel ligands that differentially activate only a subset of functions via a single receptor holds great promise for the treatment of diseases such as heart failure and hypertension. Finally, hypothetical approaches to target APJ, taking into account its downstream pathways, will be described.

Preparation of N-Phenyl-lactam Derivatives Capable of Stimulating Neurogenesis and Their Use in the Treatment of Neurological Disorders.

Title: Preparation of N-phenyl-lactam derivatives capable of stimulating neurogenesis and their use in the treatment of neurological disorders Patent/Patent Application Number: WO2015107053A1 Publication date: July 23rd, 2015 Priority Application: EP14151754.0 Priority date: January 20th, 2014 Inventors: Jakob-Roetne, R.; Wichmann, J.; Peters, J. U.; Jagasia, R. Assignee Company: Hoffmann La Roche AG Disease Area: Central Nervous System Biological Target: Neurodegenerative and neuropsychiatric diseases Summary: Neurogenesis, the process of generating new, functional neurons from neural stem cells, occurs in two neurogenic regions of the brain. The first region is the subgranular zone (SGZ) in the dentate gyrus of the hippocampus. New dentate granular cells are generated in this area. In the second area of neurogenesis, the subventricular zone (SVZ) of the lateral ventricles, new neural stem cells are converted to functional neurons that migrate through the rostral migratory system (RMS) to the olfactory bulb. Neurogenesis is very limited in other regions of the brain but may be induced after brain injury (e.g., stroke). It has been suggested that adult neurogenesis plays a role in cognition and emotional states. Further, the disruption of normal neurogenesis may be a contributing factor in the progression of a range of neurodegenerative diseases and psychiatric disorders. Decreased adult neurogenesis has been linked to chronic stress, depression, sleep deprivation, and aging. Antidepressants, however, promote adult neurogenesis. As a result of these and other related observation, it has been suggested that compounds capable of stimulating adult neurogenesis could be useful as therapeutic agents for a number of important neurodegenerative conditions and neuropsychiatric diseases. These include schizophrenia, obsessive compulsive personality disorder, major depression, bipolar disorder, anxiety disorders, epilepsy, retinal degeneration, traumatic brain injury, spinal cord injury, post-traumatic stress disorder, panic disorder, Parkinson’s disease, dementia, Alzheimer’s disease, mild cognitive impairment, chemotherapy-induced cognitive dysfunction (00chemobrain00), Down syndrome, autism spectrum disorders, hearing loss, tinnitus, spinocerebellar ataxia, amyotrophic lateral sclerosis, multiple sclerosis, Huntington’s disease, stroke, and disturbances due to radiation therapy, chronic stress, or abuse of neuro-active drugs, such as alcohol, opiates, methamphetamine, phencyclidine, and cocaine. The present disclosure describes compounds capable of stimulating neurogenesis and their use as therapeutic agents for the aforementioned conditions.

Cyclopropyl-spiro-piperidines Useful as Sodium Channel Blockers: Patent Highlight.

Published: July 30, 2012 Title: Cyclopropyl-spiro-piperidines Useful as Sodium Channel Blockers Patent Application: WO2012/047703A2 Publication Date: April 12, 2012 Priority Application: US61/389463 Priority Date: October 4, 2010 Inventors: Ho, G. D.; Tulshian, D.; Heap, C. R. Assignee: Schering Corporation Disease Area: Chronic and Neuropathic Pain Biological Target: Voltage-Gated Sodium Channel Nav1.7 Summary: Voltage-gated ion channels are critical to the generation and propagation of electrical signals and action potentials in neuronal and muscle tissue. The voltage-gated sodium channels in particular mediate the rapid depolarization of cells, creating the rising phase of an action potential, which in turn activates voltage-gated calcium and potassium channels. To date, nine voltage-gated sodium channel subtypes have been identified, and blockers of these channels have been developed as antiarrhythmic agents, anticonvulsants, antiepileptics, and local anesthetics. Voltage-gated sodium channels have also been targeted for the treatment of neuropathic pain, as it has been established that these channels play a critical role in the nerve cells associated with this condition. Specifically, it has been hypothesized that neuropathic pain is a result of increased sodium channel activity in injured nerves and that selective blockade of sodium channels such as Nav1.7 would provide therapeutic relief. The present application describes a series of cyclopropyl-spiro-piperidines useful as sodium channel blockers for the treatment of chronic and neuropathic pain. Important Compound Classes:

Fused heterocyclic compounds as ion channel modulators: patent highlight.

Priority Application: US61/361056 Priority Date: July 2, 2010 Inventors: Kobayashi, Tetsuya; Koltun, Dmitry; Notte, Gregory; Parkhill, Eric; Zablocki, Jeff Assignee Company: Gilead Science Inc. Disease Area: Cardiovascular Disease Biological Target: Voltage Gated Sodium Channel Nav1.5 Summary: Voltage-gated sodium channels play an important role in both cardiac myocytes and neuronal cells. The Nav1.5 channel is responsible for the late sodium current (INaL), and dysfunction of this channel can contribute to the development of a variety of disease states associated with abnormally high Nav1.5 activity. Ranexa, a selective INaL inhibitor, has clinical utility for the treatment of stable angina pectoris, unstable angina, and arrhythmia. This patent application discloses a series of functionalized triazolopyridin-3-ones that are useful as Nav1.5 channel inhibitors for the treatment cardiovascular diseases associated with increased Nav1.5 activity. Important Compound Classes:

The sigma-2 (σ-2) receptor: a review of recent patent applications: 2013–2018

ABSTRACT Introduction: The discovery of the sigma-2 receptor and the analogous sigma-1 receptor led to a decade-long quest to determine the true nature of this protein and novel ligands capable of modulating its activity. Despite this challenge, the sigma-2 receptor has been linked to several disease states, and multiple classes of sigma-2 ligands have been published in the 40+ years since its initial discovery. Areas covered: This review covers newly published patent applications that describe sigma-2 receptor ligands capable of modulating disease states. The aforementioned documents entered the public domain as PCT patent applications between 2013 and 2018. Expert opinion: In 2017, the sigma-2 receptor was positively identified as TMEM97 (transmembrane protein 97). The resolution of this ‘identity crisis’ will facilitate a greater understanding of the pharmacological role of sigma-2 receptor as well as support the identification of novel sigma-2 receptor ligands with potential utility as disease-modifying therapies.

Design and synthesis of functionalized piperazin-1yl-(E)-stilbenes as inhibitors of 17α-hydroxylase-C17,20-lyase (Cyp17)

The synthesis of steroid hormones is critical to human physiology and improper regulation of either the synthesis of these key molecules or activation of the associated receptors can lead to disease states. This has led to intense interest in developing compounds capable of modulating the synthesis of steroid hormones. Compounds capable of inhibiting Cyp19 (Aromatase), a key enzyme in the synthesis of estrogens, have been successfully employed as breast cancer therapies, while inhibitors of Cyp17 (17α-hydroxylase-17,20-lyase), a key enzyme in the synthesis of glucocorticoids, mineralocorticoids and steroidal sex hormones, are a key component of prostate cancer therapy. Inhibition of CYP17 has also been suggested as a possible target for the treatment of Cushing Syndrome and Metabolic Syndrome. We have identified two novel series of stilbene based CYP17 inhibitors and demonstrated that exemplary compounds in these series have pharmacokinetic properties consistent with orally delivered drugs. These findings suggest that compounds in these classes may be useful for the treatment of diseases and conditions associated with improper regulation of glucocorticoids synthesis and glucocorticoids receptor activation.

Acyl Sulfonamides NaV1.7 Blockers Useful for the Treatment of Pain

Voltage gated sodium channels (NaV) are key proteins that control the flow of sodium ions across membranes in the majority of excitable cells. Their structural features can be divided into two distinct subunits. The alpha subunit is a single large protein that contains four functional domains that controls gating and conduction. Each of these domains contains six transmembrane segment (S1–S6), four of which comprise the voltage sensing domain (S1–S4) and two that comprise the pore forming region (S5–S6). The beta subunit, however, has a single transmembrane segment and a large extracellular immunoglobin-like region. This portion of the NaV channel plays a role in controlling expression, gating, localization of the alpha subunit, and interacts with the extracellular matrix and intracellular cytoskeleton. To date, nine mammalian NaV genes have been identified, and they are referred to as NaV1.1 through NaV1.9. NaV1.7 is primarily expressed in peripheral sensory neurons and has been linked to pain sensation. Specifically, it has been demonstrated that loss of function mutations in the NaV1.7 gene (SCN9A) leads to congenital insensitivity to pain (CIP) in humans. Patients with this condition do not sense pain, even with significant injuries. Similarly, NaV 1.7 knockout mice do not respond to mechanical, inflammatory, and neuropathic pain stimuli. Gain of function of the NaV1.7 gene, however, has been linked to the inherited pain syndromes inherited erythromelalgia (IEM), paroxysmal extreme pain disorder (PEPD), and small fiber neuropathy (SFN). These finding suggest that blockade of NaV1.7 may have therapeutic value in the treatment of pain. The current disclosure describes a series of acyl sulfonamides capable of blocking NaV1.7 and their method of use for the treatment of pain.

Allosteric Modulators of Nicotinic Acetylcholine Receptors Useful for the Treatment of Cognitive Impairment

Title. Allosteric modulators of nicotinic acetylcholine receptors Patent Application Number. WO 2017/165256 A1 Publication Date. September 28th, 2017 Priority Application. US62/311,888 and US62/369,778 Priority Date. March 22nd, 2016 and August second, 2016 Inventors. Crowley, B. M.; Campbell, B. T.; Duffy, J. L.; Greshock, T. J.; Guiadeen, D. G.; Harvey, A. J.; Huff, B. C.; Leavitt, K. J.; Rada, V. L.; Sanders, J. M.; Shipe, W. D.; Suen, L. M.; Bell, I. M. Assignee Company. Merck Sharp & Dohme Corp. Disease Area. Cognitive disorders Biological Target. α7 nAChR Summary. The α7 nicotinic acetylcholine receptor (α7 nAChR) is a ligand-gated ion channel that is expressed in regions of the brain that are associated with cognition. They are found in both presynaptic and postsynaptic structures of neurons, and activation can modulate a variety of pharmacological events including neurotransmitter release, neuronal excitability, and intracellular signaling. It has been hypothesized that α7 nAChR may play a role in cognitive disorders such as Alzheimer’s disease, Parkinson’s disease, and schizophrenia. The current disclosure describes a series of positive allosteric modulators (PAMs) of α7 nAChR and their utility for the treatment of cognitive disorders. Definitions. X is selected from