| Size | Price | Stock | Qty |
|---|---|---|---|
| 5mg |
|
||
| 10mg |
|
||
| 25mg |
|
||
| 50mg |
|
||
| 100mg |
|
||
| 250mg |
|
||
| 500mg |
|
||
| Other Sizes |
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.
| Targets |
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].
|
|---|---|
| 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].
HG-10-102-01 induced dose-dependent dephosphorylation of Ser910 and Ser935 of LRRK2 in HEK293 cells stably expressing wild-type LRRK2, LRRK2[G2019S], LRRK2[A2016T], and LRRK2[G2019S + A2016T]. Substantial dephosphorylation was observed at approximately 1 μM for wild-type LRRK2 and at 0.3 μM for LRRK2[G2019S]. [1] In human lymphoblastoid cells derived from a Parkinson's disease patient homozygous for the LRRK2[G2019S] mutation, HG-10-102-01 treatment led to dephosphorylation of endogenous LRRK2 at Ser910 and Ser935 in a dose-dependent manner. [1] Similar dose-dependent dephosphorylation of endogenous LRRK2 at Ser910 and Ser935 was observed in mouse Swiss 3T3 cells and mouse embryonic fibroblast cells treated with HG-10-102-01. [1] |
| 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].
Following intraperitoneal administration in mice, HG-10-102-01 inhibited phosphorylation of Ser910 and Ser935 of endogenous LRRK2 in brain, spleen, and kidney tissues. Near-complete inhibition was observed in all tissues at a dose of 50 mg/kg. Partial inhibition in the brain was seen at doses of 30 and 10 mg/kg. [1] A chemical proteomics approach (KiNativ) in brain and spleen tissues from treated mice showed dose-related engagement of LRRK2 by HG-10-102-01. In the brain, LRRK2 inhibition was approximately 40% at 30 mg/kg and 70% at 50 and 100 mg/kg. Greater inhibition was observed in the spleen. [1] HG-10-102-01 is reported as the first compound capable of inhibiting LRRK2 phosphorylation (Ser910 and Ser935) in mouse brain following systemic administration. [1] |
| Enzyme Assay |
Biochemical inhibition of GST-tagged LRRK2 proteins (wild-type and mutants spanning residues 1326–2527) was assayed using a synthetic peptide substrate (Nictide) in the presence of 100 μM ATP. Inhibition values (IC₅₀) were determined from triplicate experiments. [1]
Selectivity profiling against a panel of 138 kinases was performed using standard radioactivity-based enzymatic assays. [1] |
| 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. HEK293 cells stably expressing GFP-tagged wild-type LRRK2 or its mutants (G2019S, A2016T, G2019S+A2016T) were treated with HG-10-102-01 or DMSO for 90 minutes. Cell lysates were subjected to immunoblotting using phospho-specific antibodies against Ser910 and Ser935 of LRRK2 and an antibody for total LRRK2 to assess inhibition of phosphorylation. [1] Human lymphoblastoid cells (from a control subject and a PD patient homozygous for LRRK2[G2019S]), mouse Swiss 3T3 cells, and mouse embryonic fibroblast cells were treated with increasing concentrations of HG-10-102-01 for 90 minutes. Cell lysates were analyzed by immunoblotting to evaluate dephosphorylation of endogenous LRRK2 at Ser910 and Ser935. [1] |
| 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 For pharmacodynamic studies, HG-10-102-01 was administered to mice via intraperitoneal injection at doses of 10, 30, 50, and 100 mg/kg. The compound was presumably dissolved in an appropriate vehicle (specific formulation not detailed in the main text). [1] At specified time points after dosing, mice were euthanized, and tissues (brain, spleen, kidney) were collected. Tissues were homogenized, and proteins were extracted for analysis by SDS-PAGE and immunoblotting using phospho-Ser910, phospho-Ser935, and total LRRK2 antibodies to evaluate target engagement and inhibition. [1] For target engagement profiling via KiNativ, brains and spleens from treated animals were lysed in a detergent-free buffer. Lysates were labeled with an ADP-acylphosphate probe, followed by trypsin digestion and quantitative mass spectrometry analysis to measure kinase labeling and inhibition. [1] |
| ADME/Pharmacokinetics |
In mice, HG-10-102-01 exhibited good oral bioavailability (67%). [1]
The compound had a short plasma elimination half-life (T₁/₂) of 0.13 hours and low plasma exposure (AUCₗₐₛₜ = 502 hng/mL). [1] After incubation with mouse liver microsomes, the half-life (T₁/₂) was only 13 minutes, indicating rapid metabolism. [1] |
| References | |
| Additional Infomation |
HG-10-102-01 is a monocarboxylic acid amide formed by the condensation of the carboxyl 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) and belongs to EC 2.7.11.1 (nonspecific serine/threonine protein kinase) inhibitors. It is an aminopyrimidine, morpholine, monocarboxylic acid amide, organochlorine compound, secondary amino compound, and aromatic ether.
HG-10-102-01 is a 2-anilino-4-methylamino-5-chloropyrimidine derivative that has been developed as a blood-brain barrier-crossing LRRK2 inhibitor for potential treatment of Parkinson's disease. [1] Unlike previous inhibitors (such as LRRK2-IN-1), this compound retains inhibitory activity against drug-resistant LRRK2 [A2016T] mutants. [1] Selectivity analysis of 451 kinases was performed using KinomeScan at a concentration of 1 μM. The results showed that, except for LRRK2 [G2019S], this compound did not interact significantly with other kinases, but only with one mutant of c-Kit (L576P), indicating that it has high selectivity. [1] This compound can cross the blood-brain barrier and inhibit LRRK2 in the brain, which distinguishes it from previous LRRK2 tool inhibitors. [1] |
| Molecular Formula |
C17H20CLN5O3
|
|---|---|
| Molecular Weight |
377.8254
|
| Exact Mass |
377.125
|
| CAS # |
1351758-81-0
|
| PubChem CID |
58539301
|
| Appearance |
White to off-white solid powder
|
| Density |
1.4±0.1 g/cm3
|
| Boiling Point |
641.1±65.0 °C at 760 mmHg
|
| Flash Point |
341.5±34.3 °C
|
| Vapour Pressure |
0.0±1.9 mmHg at 25°C
|
| Index of Refraction |
1.652
|
| LogP |
0.46
|
| Hydrogen Bond Donor Count |
2
|
| Hydrogen Bond Acceptor Count |
7
|
| Rotatable Bond Count |
5
|
| Heavy Atom Count |
26
|
| Complexity |
466
|
| Defined Atom Stereocenter Count |
0
|
| InChi Key |
YEVOZZZLKJKCCD-UHFFFAOYSA-N
|
| 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)
|
| Chemical Name |
[4-[[5-chloro-4-(methylamino)pyrimidin-2-yl]amino]-3-methoxyphenyl]-morpholin-4-ylmethanone
|
| HS Tariff Code |
2934.99.9001
|
| 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)
|
| Solubility (In Vitro) |
DMSO : ≥ 50 mg/mL (~132.33 mM)
|
|---|---|
| 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.
Products are for research use only; We do not sell to patients
Copyright 2020 InvivoChem LLC | All Rights Reserved
COA