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Purity: ≥98%
HG-10-102-01 (LRRK2 inhibitor 1) is a novel, potent and selective inhibitor of wild-type LRRK2 (leucine-rich repeat kinase 2) with an IC50 of 23.3 nM. It is also an inhibitor of the G2019S mutant form LRRK2 with an IC50 of 3.2 nM. HG-10-102-01 maintains the ability to potently inhibit the biochemical activity of wild-type and G2019S mutant LRRK2. HG-10-102-01 substantially inhibits Ser910 and Ser935 phosphorylation of both wild-type LRRK2 and G2019S mutant at a concentration of 0.1-0.3 µM in cells and is the first compound reported to be capable of inhibiting Ser910 and Ser935 phosphorylation in mouse brain following intraperitoneal delivery of doses as low as 50 mg/kg.
| ln Vitro |
The G2019S mutant and wild-type LRRK2 have their Ser910 and Ser935 phosphorylation substantially inhibited by HG-10-102-01 (0-3 μM, 90 minutes) [1].
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| ln Vivo |
In mouse kidney, spleen, and brain, HG-10-102-01 (0-100 mg/kg, IP, once) exhibits inhibitory effects on LRRK2 Ser910/Ser935 phosphorylation [1]. With a short half-life of 0.13 h, minimal plasma exposure, and good oral bioavailability (%F = 67), HG-10-102-01 (1 mg/kg IV; 10 mg/kg PO; once) was shown [1].
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| Cell Assay |
Western Blot Analysis[1]
Cell Types: HEK293 cells, Mouse Swiss 3T3 cells and mouse embryonic fibroblasts Tested Concentrations: 0, 0.01, 0.03, 0.1, 0.3, 1 and 3 μM Incubation Duration: 90 minutes Experimental Results: Induction dose dependent Inhibits Ser910 and Ser935 phosphorylation in wild-type LRRK2 and LRRK2[G2019S] stably transfected into HEK293 cells. Endogenous LRRK2 induces similar dose-dependent Ser910 and Ser935 dephosphorylation in mouse Swiss 3T3 cells and mouse embryonic fibroblasts. |
| Animal Protocol |
Animal/Disease Models: wild-type male C57BL/6 mice [1]
Doses: 0, 3, 10, 30, 50 and 100 mg/kg Route of Administration: IP, once Experimental Results: Ser910 and Ser935 of LRRK2 in all tissues were almost completely eliminated Phosphorylation has inhibitory effects on the brain at doses of 100 mg/kg and 50 mg/kg, but only partially inhibits the brain at doses of 30 mg/kg and 10 mg/kg. Animal/Disease Models: wild-type male C57BL/6 mice [1] Doses: 1 mg/kg (IV); 10 mg/kg (PO) Route of Administration: IV, PO; once (pharmacokinetic/PK/PK analysis) Experimental Results: HG- pharmacokinetic/PK/PK parameters of 10-102-01 in male C57BL/6 mice [1]. IV (1 mg/kg) PO (10 mg/kg) Tmax (h) 0.25 Cmax (ng/mL) 1330 1241 AUClast (ng/mL*h) 74.85 502.34 AUCINF (ng/mL*h) 75.06 503.41 T1/2 (h) 0.13 CL (mL/min/kg) 222.04 Vss (L/kg) 1.68 F (%) 67 |
| References | |
| Additional Infomation |
HG-10-102-01 is a monocarboxylic acid amide resulting from the formal condensation of the carboxy group of 4-{[5-chloro-4-(methylamino)pyrimidin-2-yl]amino}-3-methoxybenzoic acid with the amino group of morpholine. It is an inhibitor of leucine-rich repeat kinase 2 (LRRK2). It has a role as an EC 2.7.11.1 (non-specific serine/threonine protein kinase) inhibitor. It is an aminopyrimidine, a member of morpholines, a monocarboxylic acid amide, an organochlorine compound, a secondary amino compound and an aromatic ether.
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| Molecular Formula |
C17H20CLN5O3
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| Molecular Weight |
377.8254
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| Exact Mass |
377.125
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| CAS # |
1351758-81-0
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| PubChem CID |
58539301
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| Appearance |
White to off-white solid powder
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| Density |
1.4±0.1 g/cm3
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| Boiling Point |
641.1±65.0 °C at 760 mmHg
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| Flash Point |
341.5±34.3 °C
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| Vapour Pressure |
0.0±1.9 mmHg at 25°C
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| Index of Refraction |
1.652
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| LogP |
0.46
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
7
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| Rotatable Bond Count |
5
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| Heavy Atom Count |
26
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| Complexity |
466
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| Defined Atom Stereocenter Count |
0
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| InChi Key |
YEVOZZZLKJKCCD-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C17H20ClN5O3/c1-19-15-12(18)10-20-17(22-15)21-13-4-3-11(9-14(13)25-2)16(24)23-5-7-26-8-6-23/h3-4,9-10H,5-8H2,1-2H3,(H2,19,20,21,22)
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| Chemical Name |
[4-[[5-chloro-4-(methylamino)pyrimidin-2-yl]amino]-3-methoxyphenyl]-morpholin-4-ylmethanone
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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 : ≥ 50 mg/mL (~132.33 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2 mg/mL (5.29 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 20.0 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: ≥ 2 mg/mL (5.29 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 20.0 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. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.6467 mL | 13.2335 mL | 26.4669 mL | |
| 5 mM | 0.5293 mL | 2.6467 mL | 5.2934 mL | |
| 10 mM | 0.2647 mL | 1.3233 mL | 2.6467 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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