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| Targets |
In glial cells, MW-150 concentration-dependently prevents endogenous p38α MAPK from phosphorylating and activating the endogenous substrate MK2 [1]. In a concentration-dependent manner, MW-150 inhibits activated glial cells' enhanced production of IL-1β. MK2 and IL-1β have respective IC50 values of 332 nM and 936 nM[1].
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| ln Vitro |
In glial cells, MW-150 concentration-dependently prevents endogenous p38α MAPK from phosphorylating and activating the endogenous substrate MK2 [1]. In a concentration-dependent manner, MW-150 inhibits activated glial cells' enhanced production of IL-1β. MK2 and IL-1β have respective IC50 values of 332 nM and 936 nM[1].
MW-150 selectively inhibits p38αMAPK with a Ki of 101 nM and demonstrates negligible activity against 300 other protein and lipid kinases in a hierarchical kinome screen [1]. In LPS-activated BV-2 microglial cells, MW-150 treatment concentration-dependently suppressed phosphorylation of the endogenous p38αMAPK substrate MK2 (IC50 = 332 nM) and attenuated the downstream production of the proinflammatory cytokine IL-1β (IC50 = 936 nM) [1]. Treatment of activated glia with MW-150 engages endogenous p38αMAPK and inhibits its ability to phosphorylate MK2 in a concentration-dependent manner [1]. MW-150 showed no agonist or antagonist activity against any of the 166 GPCRs tested in a functional cellular assay [1]. High-resolution crystallography (PDB 4R3C) confirmed that MW-150 binds to the active site of human p38αMAPK, forming a key hydrogen bond with the hinge region backbone (Met109) and occupying a proximal hydrophobic pocket with its naphthyl substituent, which explains its isoform selectivity [1]. |
| ln Vivo |
APP/PS1 transgenic (Tg) mice perform better in the contextual fear conditioning test and the radial arm water maze (RAWM) when given MW-150 (2.5 mg/kg; taken orally daily for 3–4 months) [1]. In APPNLh/NLh × PSP264L/P264L knock-in mice (without amyloid precursor protein overexpression), treatment with MW-150 (2.5 mg/kg; intraperitoneal injection; once daily for 14 days) resulted in significantly reduced RAWM behavior that is indistinguishable from rats [1].
In a preventative paradigm using APP/PS1 transgenic (Tg) Alzheimer's disease (AD) mouse models, daily oral administration of MW-150 (2.5 mg/kg) from 8 weeks to 3-4 months of age suppressed deficits in both hippocampus-dependent associative memory (contextual fear conditioning) and spatial memory (radial arm water maze, RAWM) [1]. In a therapeutic paradigm using aged (11-12 months) humanized APP/PS1 knock-in (KI) AD mouse models, intraperitoneal administration of MW-150 (2.5 mg/kg, daily for 14 days) suppressed pre-existing spatial memory deficits in the RAWM test assessed 3 days after the last dose [1]. The cognitive improvements were selective, as MW-150 treatment did not affect the performance of wild-type mice, hippocampus-independent cued fear memory, sensory thresholds, motor function (visible platform test), or exploratory behavior (open field test) [1]. Treatment with MW-150 did not affect amyloid plaque load in the APP/PS1 Tg mouse model [1]. |
| Enzyme Assay |
A large-scale hierarchical kinase screen was performed, testing MW-150 against 301 representative protein and lipid kinases from all major branches of the human kinome, including isoforms of individual families. The assay utilized substrates optimized for each specific kinase. The final concentration of MW-150 in the initial screen was 20,000 nM, achieved by serial dilution from a DMSO stock. Preliminary hits (where < 40% kinase activity remained) were validated as true positives or false hits by follow-up IC50 determination. An estimated Ki value was determined for confirmed positives with IC50 < 1000 nM using kinetic analyses [1].
The inhibition constant (Ki) for p38αMAPK was estimated to be 101 nM based on kinetic analysis [1]. |
| Cell Assay |
For cellular p38αMAPK target engagement, murine BV-2 microglial cells were stimulated with 100 ng/mL LPS in the absence or presence of increasing concentrations of MW-150. Cells were harvested after 1 hour of stimulation for analysis of phosphorylated MK2 (pMK2) levels by ELISA. The downstream functional effect was assessed by measuring the production of the proinflammatory cytokine IL-1β in cell supernatants after 16 hours of LPS stimulation via ELISA [1].
Caco-2 cell permeability and P-glycoprotein (P-gp) efflux pump substrate status were assessed using a bidirectional transport assay. MW-150 (5 µM) was added to either the apical (A) or basolateral (B) side, and permeation to the opposite side was measured over 2 hours by LC-MS/MS. The assay was also performed in the presence of the P-gp inhibitor valspodar (1 µM) to determine substrate status [1]. MDCK cell permeability and Breast Cancer Resistance Protein (BCRP) efflux pump substrate status were similarly assessed using a bidirectional transport assay over 2 hours, with and without the BCRP inhibitor Ko143 (10 µM) [1]. |
| Animal Protocol |
Animal/Disease Models: APP/PS1 transgenic (Tg) mice (overexpressing β-amyloid) [1]
Doses: 2.5 mg/kg Route of Administration: daily oral administration; 3-4 months (until cognitive impairment occurs) Experimental Results: Improved performance of Tg mice in radial arm water maze (RAWM) and contextual fear conditioning tests. For efficacy testing in APP/PS1 transgenic (Tg) mice, wild-type and APP/PS1 littermate mice received daily oral administration of either saline vehicle or MW-150 (2.5 mg/kg) starting at 8 weeks of age and continuing until behavioral testing at 3-4 months of age. Behavioral assessments included the radial arm water maze (RAWM) for spatial memory and contextual fear conditioning for associative memory [1]. For efficacy testing in aged APP/PS1 knock-in (KI) mice, 11-12 month old wild-type and KI mice received daily intraperitoneal injections of either vehicle or MW-150 (2.5 mg/kg) for 14 days. Spatial memory was assessed using the RAWM task starting 3 days after the final administration [1]. For pharmacokinetic screening, male Sprague-Dawley rats were fasted and administered MW-150 intravenously or orally at a dose of 5 mg/kg. Blood samples were collected via jugular vein cannulation at multiple time points up to 6 hours post-dose for plasma concentration analysis by LC-MS/MS [1]. For brain penetration assessment, male Sprague-Dawley rats received a single oral dose of MW-150 (5 mg/kg). Plasma and whole brain tissue were collected 3 hours post-administration. Brain tissue was homogenized, and concentrations of MW-150 in plasma and brain homogenate were determined by LC-MS/MS [1]. A preliminary safety pharmacology screen was conducted using a modified SHIRPA test paradigm. C57BL/6 mice were administered saline (control) or MW-150 at doses of 50 and 150 mg/kg (20- and 60-fold above the efficacy dose), and clinical observations were documented over 24 hours [1]. |
| ADME/Pharmacokinetics |
MW-150 exhibited good metabolic stability in human liver microsomes (HLM) with a half-life (T1/2) > 60 min and in rat liver microsomes (RLM) with a T1/2 of 43 ± 4 min. The estimated intrinsic clearance (CLint) was 0.02 ± 0.00 mL/min/mg protein [1]. MW-150 was not found to be a substrate for any of the seven major human cytochrome P450 (CYP) isoenzymes (CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6, 3A4) recommended by the FDA, and each isoenzyme had a half-life (T1/2) greater than 60 min [1]. MW-150 showed no inhibitory activity against any of the seven major CYP isoenzymes at a concentration of 10 µM [1].
MW-150 showed high permeability in Caco-2 cell permeability assays (Papp A→B = 33.5 x 10^-6 cm/s) and was not a substrate of P-gp efflux transporter (efflux ratio = 0.9, unchanged after inhibitor treatment) [1]. MW-150 also showed high permeability in MDCK cell assays (Papp A→B = 20.7 x 10^-6 cm/s) and was not a substrate of BCRP efflux transporter (efflux ratio = 1.2, decreased to 0.9 after inhibitor treatment) [1]. In rat pharmacokinetic screening, MW-150 had a plasma half-life > 3 hours and oral bioavailability > 50% at a dose of 5 mg/kg [1]. Three hours after a single oral dose of 5 mg/kg in rats, the brain/plasma ratio of MW-150 was >0.9, indicating that it can cross the blood-brain barrier well [1]. The acid dissociation constant (pKa) of MW-150 was determined to be 3.83 and 7.27 [1]. The hydrochloride form of MW-150 has acceptable water solubility (>1 mg/mL) and chemical stability over a wide pH range (1–13) at 37°C for 24 hours [1]. |
| Toxicity/Toxicokinetics |
In the Ames bacterial reverse mutation assay (with/without metabolic activation), using Salmonella Typhimurium strains TA98 and TA100 at concentrations up to 5 µg/plate, MW-150 was negative, indicating no mutagenicity under the test conditions [1]. In the mouse modified SHIRPA assay, no adverse events or differences in motor activity (total distance of movement, center and edge occupancy) were detected during the 24-hour observation period after administration of MW-150 at doses up to 150 mg/kg (60 times the effective dose) [1]. At concentrations up to 25 µM, MW-150 did not show inhibitory effects on monoamine oxidase A or B (MAO-A/MAO-B) [1]. MW-150 is not a substrate or inhibitor of key cytochrome P450 enzymes. This reduces the risk of drug interactions [1].
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| References | |
| Additional Infomation |
MW-150 is a novel, subtype-selective p38αMAPK inhibitor developed through scaffold repositioning and structure-based drug design of a previously experimental central nervous system-penetrating drug (MW189) [1]. It represents a potential therapeutic strategy for Alzheimer's disease and other central nervous system disorders involving synaptic dysfunction, as it can alleviate stress-induced pathophysiological responses in neurons and glial cells within synaptic units [1]. The high selectivity of MW-150 is attributed to its unique binding mode, which combines typical hydrogen-bonded interactions with the kinase hinge region with extensive filling of the proximal hydrophobic pocket by its 2-naphthyl substituent, a property not found in ATP [1]. The compound possesses favorable pharmacological properties (good oral bioavailability, central nervous system penetration, and no CYP metabolic impairment), supporting its potential as a novel drug for further investigation. (IND) - Supporting the development of drugs for complex central nervous system disorders [1].
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| Molecular Formula |
C24H23N5
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|---|---|
| Molecular Weight |
381.472924470901
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| Exact Mass |
381.195
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| CAS # |
1628502-91-9
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| Related CAS # |
MW-150 hydrochloride;1923773-01-6;MW-150 dihydrochloride dihydrate;1661020-92-3
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| PubChem CID |
86270361
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| Appearance |
Off-white to light yellow solid powder
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| LogP |
3.6
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| Hydrogen Bond Donor Count |
0
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| Hydrogen Bond Acceptor Count |
5
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| Rotatable Bond Count |
3
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| Heavy Atom Count |
29
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| Complexity |
513
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| Defined Atom Stereocenter Count |
0
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| SMILES |
N1(C2=CC(C3C=CN=CC=3)=C(C3C=CC4C=CC=CC=4C=3)N=N2)CCN(C)CC1
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| InChi Key |
CIIVUDIZZJLXCN-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C24H23N5/c1-28-12-14-29(15-13-28)23-17-22(19-8-10-25-11-9-19)24(27-26-23)21-7-6-18-4-2-3-5-20(18)16-21/h2-11,16-17H,12-15H2,1H3
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| Chemical Name |
6-(4-methylpiperazin-1-yl)-3-naphthalen-2-yl-4-pyridin-4-ylpyridazine
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
DMSO : ~40 mg/mL (~104.86 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 3 mg/mL (7.86 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 30.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 3 mg/mL (7.86 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 30.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 3 mg/mL (7.86 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.6214 mL | 13.1072 mL | 26.2144 mL | |
| 5 mM | 0.5243 mL | 2.6214 mL | 5.2429 mL | |
| 10 mM | 0.2621 mL | 1.3107 mL | 2.6214 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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