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| Targets |
The primary target of JH-II-127 is leucine-rich repeat kinase 2 (LRRK2), a multi-domain protein kinase implicated in the pathogenesis of Parkinson's disease and other neurodegenerative disorders. JH-II-127 is a potent and selective inhibitor of both wild-type and G2019S mutant LRRK2. It inhibits WT LRRK2 with an IC50 of 6.6 nM, G2019S LRRK2 with an IC50 of 2.2 nM, and A2016T LRRK2 with an IC50 of 47.7 nM.
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| ln Vitro |
In HEK293 cells, JH-II-127 (0.03, 0.1, 0.3, 1, 3 µM; 90 minutes) suppresses LRRK2 [1]. In mouse Swiss 3T3 cells, endogenously produced LRRK2 is inhibited by JH-II-127 (0.3, 1, 3 µM; 90 minutes) [1].
In vitro, JH-II-127 demonstrates potent inhibition of LRRK2 kinase activity. It inhibits wild-type LRRK2 with an IC50 of 6.6 nM, G2019S LRRK2 with an IC50 of 2.2 nM, and A2016T LRRK2 with an IC50 of 47.7 nM. The compound shows selectivity for LRRK2 over other kinases. Its potent inhibition of both wild-type and mutant LRRK2 makes it a valuable tool for studying LRRK2 biology and potential therapeutic applications. |
| ln Vivo |
JH-II-127 (100 mg/kg; i.p.; single dosage) produces nearly full dephosphorylation of LRRK2 Ser935 in all tissues, including brain [1]. 1.19 Pharmacokinetic characteristics of JH-II-127 in wild-type male C57BL/6 mice [1]. Matrix route Tmax (h) C0/Cmax (ng/mL) AUCLast (h·ng/mL) AUGINF (h·ng/mL) T1/2 (h) CL (mL/min/kg) Vss (L/kg) Plasma IV (2 mg/kg) - 1604.47 532.67 535.57 0.66 62.24 1.73 Plasma PO (10 mg/kg) 1 802.72 3094.58 3867.07 - - - Brain IV (2 mg/kg) - 1343.6 239.31 246.47 0.23 1 35. 24 1.7 Brain PO (10 mg/kg) 1 247.35 688.21 762.38 - - -
No specific in vivo activity data is publicly available for JH-II-127. As a brain penetrant LRRK2 inhibitor, it would be expected to reach central nervous system targets following systemic administration. The compound is orally active, suggesting favorable oral bioavailability. However, specific in vivo efficacy data from animal models is not detailed in the available sources. |
| Enzyme Assay |
For LRRK2 inhibitors, standard cell-free assays involve measuring the kinase activity of recombinant LRRK2 (wild-type or mutant forms) using peptide substrates. The compound is incubated with the enzyme, ATP, and substrate, and phosphorylation is detected by radioactive or fluorescent methods to determine IC50 values. Selectivity is assessed by profiling against a panel of kinases.
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| Cell Assay |
Western Blot Analysis[1]
Cell Types: HEK293 cells (expressing GFP-LRRK2, GFP-LRRK2[G2019S], GFP-LRRK2[G2019S + A2016T] and GFP-LRRK2[A2016T], respectively. Tested Concentrations: 0.03, 0.1, 0.3, 1, 3 µM Incubation Duration: 90 minutes Experimental Results: Induced dose-dependent inhibition of Ser910 and Ser935 phosphorylation in wild-type LRRK2 and LRRK2[G2019S] stably transfected into HEK293 cells. For wild-type LRRK2 and LRRK2[G2019S], at ca. Inhibits phosphorylation of Ser910 and Ser935 at 0.3 μM. Induces dephosphorylation of Ser910 and Ser935 at concentrations of 0.3-1 μM in drug-resistant LRRK2[A2016T + G2019S] and LRRK2[A2016T] mutants. Western Blot Analysis[1] Cell Types: Mouse Swiss 3T3 Cell Tested Concentrations: 0.03, 0.1, 0.3, 1, 3 µM Incubation Duration: 90 min Experimental Results: Induces similar dose-dependent Ser935 dephosphorylation of endogenous LRRK2. For LRRK2 inhibitors, standard cellular assays involve treatment of cells with the test compound for 4-24 hours. LRRK2 autophosphorylation (e.g., Ser1292) and phosphorylation of downstream substrates (e.g., Rab10) are measured by western blot to assess target engagement. Cell viability and cytotoxicity are assessed using standard assays. |
| Animal Protocol |
Animal/Disease Models: wild-type male C57BL/6 mice [1].
Doses: 2 mg/kg (intravenous (iv) (iv)injection); 10 mg/kg (oral); 10, 30, 100 mg/kg (intraperitoneal (ip) injection) Route of Administration: intravenous (iv) (iv)and intraperitoneal (ip) injection; oral administration; single. Experimental Results: intraperitoneal (ip) injection of 100 mg/kg resulted in near-complete dephosphorylation of LRRK2 Ser935 in all tissues, including the brain, and at 30 mg/kg resulted in near-complete inhibition in all tissues, but not at 10 mg/kg. There was only partial inhibition in the brain at kg doses. Exhibits good oral bioavailability. For in vivo evaluation of LRRK2 inhibitors, standard animal models include transgenic mouse models expressing mutant LRRK2 (e.g., G2019S) or models of Parkinson's disease. The compound is typically administered orally for 2-4 weeks. LRRK2 phosphorylation, downstream signaling, and behavioral and pathological endpoints are assessed. |
| ADME/Pharmacokinetics |
JH-II-127 has a molecular weight of 416.86 and formula C19H21ClN6O3. As a small molecule with moderate lipophilicity, it would be expected to have reasonable cell permeability and oral bioavailability. The compound is brain penetrant. Comprehensive pharmacokinetic studies would be required for therapeutic development.
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| Toxicity/Toxicokinetics |
No detailed toxicology data is publicly available for JH-II-127. As a research compound targeting LRRK2, standard preclinical toxicology would be required for therapeutic development. The compound's selectivity for LRRK2 may contribute to a manageable safety profile, though potential off-target effects would need to be assessed. The compound is for research use only and not for therapeutic applications.
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| References | |
| Additional Infomation |
JH-II-127 is a highly potent, selective, and brain penetrant LRRK2 inhibitor. It inhibits wild-type LRRK2, G2019S LRRK2, and A2016T LRRK2 with IC50 values of 6.6 nM, 2.2 nM, and 47.7 nM, respectively. The compound is a Pyrrolopyrimidine derivative. No regulatory approval for therapeutic use has been identified.
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| Molecular Formula |
C19H21CLN6O3
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| Molecular Weight |
416.87
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| Exact Mass |
416.136
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| CAS # |
1700693-08-8
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| PubChem CID |
112499966
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| Appearance |
Light yellow to yellow solid powder
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| Density |
1.5±0.1 g/cm3
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| Boiling Point |
581.4±60.0 °C at 760 mmHg
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| Flash Point |
305.4±32.9 °C
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| Vapour Pressure |
0.0±1.6 mmHg at 25°C
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| Index of Refraction |
1.701
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| LogP |
-0.68
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| Hydrogen Bond Donor Count |
3
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| Hydrogen Bond Acceptor Count |
7
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| Rotatable Bond Count |
5
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| Heavy Atom Count |
29
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| Complexity |
566
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| Defined Atom Stereocenter Count |
0
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| SMILES |
CNC1=NC(=NC2=C1C(=CN2)Cl)NC3=C(C=C(C=C3)C(=O)N4CCOCC4)OC
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| InChi Key |
HUEKBQXFNHWTQQ-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C19H21ClN6O3/c1-21-16-15-12(20)10-22-17(15)25-19(24-16)23-13-4-3-11(9-14(13)28-2)18(27)26-5-7-29-8-6-26/h3-4,9-10H,5-8H2,1-2H3,(H3,21,22,23,24,25)
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| Chemical Name |
[4-[[5-chloro-4-(methylamino)-7H-pyrrolo[2,3-d]pyrimidin-2-yl]amino]-3-methoxyphenyl]-morpholin-4-ylmethanone
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| Synonyms |
JH-II127; JH-II 127; JH-II-127
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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 : ~110 mg/mL (~263.88 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.75 mg/mL (6.60 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 27.5 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: ≥ 2.75 mg/mL (6.60 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (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 27.5 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.3988 mL | 11.9941 mL | 23.9883 mL | |
| 5 mM | 0.4798 mL | 2.3988 mL | 4.7977 mL | |
| 10 mM | 0.2399 mL | 1.1994 mL | 2.3988 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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