Therapeutics

MW151

Overview

Name: MW151
Synonyms: MW01-2-151SRM, Minozac, MW01-2-151WH, compound 17
Chemical Name: 2-(4-(4-methyl-6-phenylpyridazin-3-yl)piperazin-1-yl) pyrimidine
Therapy Type: Small Molecule (timeline)
Target Type: Inflammation (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 1)
Company: ImmunoChem Therapeutics, LLC

Background

MW151 is an orally available, brain-penetrant, anti-inflammatory compound. Its target is undisclosed. MW151 was discovered by screening and optimizing compounds that inhibit proinflammatory cytokine production in activated glia cells in culture (Wing et al., 2006). MW151 does not block anti-inflammatory cytokines.

Neuroinflammation involving glial activation occurs in Alzheimer’s and other neurodegenerative diseases, and contributes to disease pathology and cognitive decline.

In preclinical work, MW151 suppressed microglia and astrocyte activation, and upregulation of the inflammatory cytokines IL1β, TNFα, and S100b caused oligomeric human Aβ42 infusion into mouse brain. MW151 prevented loss of synaptic proteins and hippocampal-dependent behavioral deficits in the mice (Hu et al., 2007).

In an APP/PS1 transgenic mouse model, MW151 treatment early in life reduced subsequent neuroinflammation, preventing losses of synapses and synaptic plasticity. The drug did not affect amyloid plaque load (Bachstetter et al., 2012). MW151 also reduced acute inflammation after traumatic brain injury in the APP/PS1 mice, and improved cognitive outcomes, without lessening Aβ accumulation (Webster et al., 2015).

MW151 quelled inflammation, prevented seizures, and boosted cognition in models of traumatic brain injury (Lloyd et al., 2008; Bachstetter et al., 2015; Bachstetter et al., 2016; Chrzaszcz et al., 2010), and radiation- or seizure-induced cognitive impairment (Jenrow et al., 2013; Somera-Molina et al., 2009).

The drug lessened paralysis in a model of multiple sclerosis (Karpus et al., 2008) and enhanced efficacy of gene therapy in a mouse model for a neurodegenerative lysosomal storage disease (Macauley et al., 2014).

Findings

In October 2019, a Phase 1 first-in-human study of MW151 began at Duke University. Supported by the National Institute on Aging, the trial will randomize 40 healthy adults to a single dose of 10, 20, 40, 80 or 160 mg, or placebo in capsule form. Safety will be monitored by adverse events, physical examination findings, clinical laboratory results, vital signs, and electrocardiograms (ECGs). Pharmacokinetics will be assessed. The trial is slated to end in January 2021.

MW189, an intravenous formulation of MW151, is being tested in a Phase 1 trial in healthy adults, also at Duke. MW189 is intended for acute indications such as traumatic brain injury (May 2017 conference news).

For details on MW151 trials, see clinicaltrials.gov.

Last Updated: 20 Apr 2020

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References

News Citations

  1. Non-Amyloid Treatments: Inflammation, Epigenetics, Regeneration

Paper Citations

  1. . De novo and molecular target-independent discovery of orally bioavailable lead compounds for neurological disorders. Curr Alzheimer Res. 2006 Jul;3(3):205-14. PubMed.
  2. . Development of a novel therapeutic suppressor of brain proinflammatory cytokine up-regulation that attenuates synaptic dysfunction and behavioral deficits. Bioorg Med Chem Lett. 2007 Jan 15;17(2):414-8. PubMed.
  3. . Early stage drug treatment that normalizes proinflammatory cytokine production attenuates synaptic dysfunction in a mouse model that exhibits age-dependent progression of Alzheimer's disease-related pathology. J Neurosci. 2012 Jul 25;32(30):10201-10. PubMed.
  4. . Closed head injury in an age-related Alzheimer mouse model leads to an altered neuroinflammatory response and persistent cognitive impairment. J Neurosci. 2015 Apr 22;35(16):6554-69. PubMed.
  5. . Suppression of acute proinflammatory cytokine and chemokine upregulation by post-injury administration of a novel small molecule improves long-term neurologic outcome in a mouse model of traumatic brain injury. J Neuroinflammation. 2008 Jun 30;5:28. PubMed.
  6. . Attenuation of traumatic brain injury-induced cognitive impairment in mice by targeting increased cytokine levels with a small molecule experimental therapeutic. J Neuroinflammation. 2015 Apr 10;12:69. PubMed.
  7. . MW151 Inhibited IL-1β Levels after Traumatic Brain Injury with No Effect on Microglia Physiological Responses. PLoS One. 2016;11(2):e0149451. Epub 2016 Feb 12 PubMed.
  8. . Minozac treatment prevents increased seizure susceptibility in a mouse "two-hit" model of closed skull traumatic brain injury and electroconvulsive shock-induced seizures. J Neurotrauma. 2010 Jul;27(7):1283-95. PubMed.
  9. . Selective inhibition of microglia-mediated neuroinflammation mitigates radiation-induced cognitive impairment. Radiat Res. 2013 May;179(5):549-56. Epub 2013 Apr 5 PubMed.
  10. . Enhanced microglial activation and proinflammatory cytokine upregulation are linked to increased susceptibility to seizures and neurologic injury in a 'two-hit' seizure model. Brain Res. 2009 Jul 28;1282:162-72. Epub 2009 Jun 6 PubMed.
  11. . Inhibition of experimental autoimmune encephalomyelitis by a novel small molecular weight proinflammatory cytokine suppressing drug. J Neuroimmunol. 2008 Oct 15;203(1):73-8. PubMed.
  12. . An anti-neuroinflammatory that targets dysregulated glia enhances the efficacy of CNS-directed gene therapy in murine infantile neuronal ceroid lipofuscinosis. J Neurosci. 2014 Sep 24;34(39):13077-82. PubMed.

External Citations

  1. Phase 1 trial
  2. clinicaltrials.gov

Further Reading

No Available Further Reading