The Minozac Scaffold
For the MORE technically inclined follow the LINK.... https://www.jneuroinflammation.com/content/4/1/21
TT-223 Stand Alone has Better Results than either Byetta OR Liraglutide (Novo's STILL UNAPPROVED GLP1 Analogue)(STILL UNAPPROVED WTF?) did at this stage of the game. Way better when you take into account the Nausea that they both induce in Humans.......whereas TT-223 Does Not have ANY Nausea related adverse events in HUMANS. THATS HUGE!!
Ongoing DLP Studies just about complete......
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The Minozac Scaffold....
A novel p38α MAPK inhibitor (MINOZAC) suppresses brain proinflammatory cytokine up-regulation and attenuates synaptic dysfunction and behavioral deficits ........
Abstract
Background
An accumulating body of evidence is consistent with the hypothesis that excessive or prolonged increases in proinflammatory cytokine production by activated glia is a contributor to the progression of pathophysiology that is causally linked to synaptic dysfunction and hippocampal behavior deficits in neurodegenerative diseases such as Alzheimer's disease (AD). This raises the opportunity for the development of new classes of potentially disease-modifying therapeutics. A logical candidate CNS target is p38α MAPK, a well-established drug discovery molecular target for altering proinflammatory cytokine cascades in peripheral tissue disorders. Activated p38 MAPK is seen in human AD brain tissue and in AD-relevant animal models, and cell culture studies strongly implicate p38 MAPK in the increased production of proinflammatory cytokines by glia activated with human amyloid-beta (Aβ) and other disease-relevant stressors. However, the vast majority of small molecule drugs do not have sufficient penetrance of the blood-brain barrier to allow their use as in vivo research tools or as therapeutics for neurodegenerative disorders. The goal of this study was to test the hypothesis that brain p38α MAPK is a potential in vivo target for orally bioavailable, small molecules capable of suppressing excessive cytokine production by activated glia back towards homeostasis, allowing an improvement in neurologic outcomes.
Methods
A novel synthetic small molecule based on a molecular scaffold used previously was designed, synthesized, and subjected to analyses to demonstrate its potential in vivo bioavailability, metabolic stability, safety and brain uptake. Testing for in vivo efficacy used an AD-relevant mouse model.
Results
A novel, CNS-penetrant, non-toxic, orally bioavailable, small molecule inhibitor of p38α MAPK (MW01-2-069A-SRM) was developed. Oral administration of the compound at a low dose (2.5 mg/kg) resulted in attenuation of excessive proinflammatory cytokine production in the hippocampus back towards normal in the animal model. Animals with attenuated cytokine production had reductions in synaptic dysfunction and hippocampus-dependent behavioral deficits.
Conclusion
The p38α MAPK pathway is quantitatively important in the Aβ-induced production of proinflammatory cytokines in hippocampus, and brain p38α MAPK is a viable molecular target for future development of potential disease-modifying therapeutics in AD and related neurodegenerative disorders.
Background
Up-regulation of proinflammatory cytokine production by activated glia has been implicated in disease progression in a variety of chronic neurodegenerative disorders, including Alzheimer's disease (AD), Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, and HIV-associated dementia [for selected reviews, see [1-10]]. In AD, studies with clinical samples and investigations using animal models provided strong correlations of early increases in proinflammatory cytokine levels, especially interleukin-1β (IL-1β) and tumor necrosis factor α (TNFα), prior to neurologic sequelae [5,11,12]. Causal relationships were established by demonstration of a worsening of neuropathologic outcomes as a result of experimentally manipulated increases in proinflammatory cytokines or an improvement of outcomes with treatments that decrease cytokine levels. The former includes the use of transgenic and knockout mouse models subjected to AD-relevant stress [13,14], or direct administration of cytokines to the brain [15-19]. The latter includes treatment with small molecules that suppress excessive cytokine production by glia back towards basal [20-23]. This accumulating body of evidence is the foundation of current efforts to decipher which combinations of disease-relevant stressors and signal transduction pathways might be amenable to therapeutic interventions that modulate cytokine production [for review, see [1]].
Current drugs approved for human use to modulate cytokine function are macromolecules [e.g., see [24,25]]. Although a clinical feasibility study in AD patients raises the potential of positive neurologic outcomes [26], macromolecular drugs have a number of disadvantages for clinical use in chronic CNS disorders, including high cost and inconvenient dosing regimens. Thus, there is a critical need for orally active, brain-penetrant, small molecule therapeutics that can suppress excessive proinflammatory cytokine production by glia back towards homeostasis without being pan-suppressors, such as steroids with their untoward side effects and poor ability to alter pathophysiology progression [27,28].
Recently, we developed an experimental therapeutic whose mechanism of action is reduction of excessive proinflammatory cytokine levels in the hippocampus back towards basal levels, with a resultant attenuation of synaptic dysfunction and hippocampus-dependent behavior alteration [22,23,29]. The drug, Minozac, is in clinical development. Minozac discovery and development used a de novo compound discovery platform interfaced with hierarchal biological screens for oral bioavailability, toxicity, brain penetrance, and stability. Compounds emerging from the platform were tested for efficacy in animal models of CNS disorders [22,23,30], employing the more unbiased functional approach to drug discovery that has proven attractive for complex disorders and initial therapy development in areas of unmet need [31,32]. Minozac, therefore, provides a precedent for selective targeting of increased proinflammatory production with positive neurologic outcomes in an AD-related neurodegenerative disease model. Minozac is not an inhibitor of p38α MAPK, an established drug discovery target for peripheral tissue diseases, such as rheumatoid arthritis, that are also characterized by increased proinflammatory cytokine production as part of disease progression [for reviews, see [33-38]]. In contrast to the extensive knowledgebase for peripheral tissue disorders, less is known about the in vivo contributions of the p38α MAPK signaling cascade to the brain cytokine overproduction and neurodegenerative sequelae in CNS disorders such as AD, or the potential of p38α MAPK as a therapeutic target for such disorders [for reviews, see [39,40]].
The p38 MAPK signaling cascade is activated in AD as demonstrated by staining of AD brain tissue samples for phosphorylated (activated) p38 MAPK or upstream components of the pathway [19,41-46]. Activation of the p38 MAPK pathway is also seen in AD-relevant animal models [47-51]. However, causative linkages between MAPK pathway activation and proinflammatory cytokine production by glia is mainly via cell culture studies. For example, stimulation of glial cell cultures with Aβ1–42 induces p38 MAPK activation [52-56] with a later induction of proinflammatory cytokines, and p38 MAPK inhibitors block the increase [see, e.g., [53,56-58]]. Therefore, there is a body of strongly suggestive evidence that brain p38α MAPK may be a viable therapeutic target for AD and related neurodegenerative disorders. Further pursuit of this hypothesis requires the use of brain-penetrant, small molecule p38α MAPK inhibitors to demonstrate restoration of Aβ-induced up-regulation of brain cytokine production back towards normal, with an associated improvement in neurologic outcomes.
In order to fill this void in knowledge and provide a foundation for future therapeutic development efforts, we employed the same chemical scaffold used for Minozac development to design and produce a novel p38α MAPK inhibitor with potential for use in studies of brain pathology alteration in AD-relevant animal models. The rationale for using chemical diversification of the Minozac scaffold is two-fold. First, analog design is one of the most successful for the development of novel small molecule drugs, with approximately two-thirds of all small molecule sales resulting from the analog approach [59]. Second, greater than 98% of small molecule drugs have inadequate blood-brain barrier penetrance [60]. Minozac [22] and the lead compound from which it was developed, MW01-5-188WH [23], use a common scaffold and have good blood-brain barrier penetrance, justifying redundant use of this scaffold in attempts to discover a p38α MAPK targeted inhibitor for altering CNS pathophysiology.
We describe here the development of a novel, orally bioavailable, brain-penetrant, non-toxic p38α MAPK inhibitor and its in vivo use at a low oral dose to attenuate human Aβ-induced increases in mouse hippocampus cytokine levels, consistent with the proposed mechanism of inhibitor action. Improved neurologic endpoints support the hypothesis that p38α MAPK is a viable target for future drug development.
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