Therapeutics

MW151

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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 after 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). In a mouse model of mixed vascular and amyloid pathology, the compound reduced inflammation and improved markers of hippocampal metabolism; the mice were reported to have shown a trend toward improved memory functions (Braun et al., 2022).

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 safety and pharmacokinetic study of MW151 began at Duke University, with support from the NIH SBIR/STTR funding program. The trial randomized 40 healthy adults to a single dose of 10, 20, 40, 80, or 160 mg, or placebo, in capsule form. The trial ended in September 2021, and results are posted on clinicaltrials.gov. The study reported no serious adverse events related to drug. The most common side effect was headache at the higher doses. Blood drug levels were dose-proportional.

MW189, an intravenous formulation of MW151, was tested in a Phase 1 trial in healthy adults, also at Duke (Van Eldik et al., 2021). THis formulation has now progressed to Phase 2 in people with hemorrhagic stroke. MW189 is intended for acute indications including traumatic brain injury (May 2017 conference news).

In July 2022, another Phase 1 began testing MW151 to treat cognitive impairment induced by whole-brain radiation in cancer patients.

For details on MW151 trials, see clinicaltrials.gov.

Last Updated: 08 Feb 2023

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References

News Citations

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

Paper Citations

  1. Van Eldik LJ, Sawaki L, Bowen K, Laskowitz DT, Noveck RJ, Hauser B, Jordan L, Spears TG, Wu H, Watt K, Raja S, Roy SM, Watterson DM, Guptill JT. First-in-Human Studies of MW01-6-189WH, a Brain-Penetrant, Antineuroinflammatory Small-Molecule Drug Candidate: Phase 1 Safety, Tolerability, Pharmacokinetic, and Pharmacodynamic Studies in Healthy Adult Volunteers. Clin Pharmacol Drug Dev. 2021 Feb;10(2):131-143. Epub 2020 Apr 7 PubMed.
  2. Wing LK, Behanna HA, Van Eldik LJ, Watterson DM, Ralay Ranaivo H. 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.
  3. Hu W, Ralay Ranaivo H, Roy SM, Behanna HA, Wing LK, Munoz L, Guo L, Van Eldik LJ, Watterson DM. 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.
  4. Bachstetter AD, Norris CM, Sompol P, Wilcock DM, Goulding D, Neltner JH, St Clair D, Watterson DM, Van Eldik LJ. 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.
  5. Webster SJ, Van Eldik LJ, Watterson DM, Bachstetter AD. 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.
  6. Braun DJ, Powell DK, McLouth CJ, Roy SM, Watterson DM, Van Eldik LJ. Therapeutic treatment with the anti-inflammatory drug candidate MW151 may partially reduce memory impairment and normalizes hippocampal metabolic markers in a mouse model of comorbid amyloid and vascular pathology. PLoS One. 2022;17(1):e0262474. Epub 2022 Jan 26 PubMed.
  7. Lloyd E, Somera-Molina K, Van Eldik LJ, Watterson DM, Wainwright MS. 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.
  8. Bachstetter AD, Webster SJ, Goulding DS, Morton JE, Watterson DM, Van Eldik LJ. 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.
  9. Bachstetter AD, Zhou Z, Rowe RK, Xing B, Goulding DS, Conley AN, Sompol P, Meier S, Abisambra JF, Lifshitz J, Watterson DM, Van Eldik LJ. 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.
  10. Chrzaszcz M, Venkatesan C, Dragisic T, Watterson DM, Wainwright MS. 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.
  11. Jenrow KA, Brown SL, Lapanowski K, Naei H, Kolozsvary A, Kim JH. Selective inhibition of microglia-mediated neuroinflammation mitigates radiation-induced cognitive impairment. Radiat Res. 2013 May;179(5):549-56. Epub 2013 Apr 5 PubMed.
  12. Somera-Molina KC, Nair S, Van Eldik LJ, Watterson DM, Wainwright MS. 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.
  13. Karpus WJ, Reynolds N, Behanna HA, Van Eldik LJ, Watterson DM. 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.
  14. Macauley SL, Wong AM, Shyng C, Augner DP, Dearborn JT, Pearse Y, Roberts MS, Fowler SC, Cooper JD, Watterson DM, Sands MS. 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. SBIR/STTR
  2. Phase 1 trial
  3. Phase 2
  4. clinicaltrials.gov

Further Reading

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