GNE-9605 (GNE 9605; GNE9605) is a novel, brain-penetrant, highly potent and selective leucine-rich repeat kinase 2 (LRRK2) inhibitor with anti-PD (Parkinson's disease) activity. It inhibits LRRK2 with a Ki and an IC50 of 2 nM and 19 nM, respectively. In human hepatocytes and liver microsomes, GNE-9605 exhibited excellent human metabolic stability.
Physicochemical Properties
| Molecular Formula | C17H20CLF4N7O | |
| Molecular Weight | 449.83 | |
| Exact Mass | 449.135 | |
| CAS # | 1536200-31-3 | |
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| PubChem CID | 76328936 | |
| Appearance | White to off-white solid powder | |
| Density | 1.7±0.1 g/cm3 | |
| Boiling Point | 587.9±60.0 °C at 760 mmHg | |
| Flash Point | 309.4±32.9 °C | |
| Vapour Pressure | 0.0±1.6 mmHg at 25°C | |
| Index of Refraction | 1.663 | |
| LogP | 1.15 | |
| Hydrogen Bond Donor Count | 2 | |
| Hydrogen Bond Acceptor Count | 11 | |
| Rotatable Bond Count | 5 | |
| Heavy Atom Count | 30 | |
| Complexity | 587 | |
| Defined Atom Stereocenter Count | 2 | |
| SMILES | CNC1=NC(=NC=C1C(F)(F)F)NC2=C(N(N=C2)[C@H]3CCN(C[C@@H]3F)C4COC4)Cl |
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| InChi Key | PUXPEQJKNAWNQA-AAEUAGOBSA-N | |
| InChi Code | InChI=1S/C17H20ClF4N7O/c1-23-15-10(17(20,21)22)4-24-16(27-15)26-12-5-25-29(14(12)18)13-2-3-28(6-11(13)19)9-7-30-8-9/h4-5,9,11,13H,2-3,6-8H2,1H3,(H2,23,24,26,27)/t11-,13-/m0/s1 | |
| Chemical Name | 2-N-[5-chloro-1-[(3S,4S)-3-fluoro-1-(oxetan-3-yl)piperidin-4-yl]pyrazol-4-yl]-4-N-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine | |
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| 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 |
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| Shipping Condition | Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs) |
Biological Activity
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| ln Vivo | LRRK2 Ser1292 autophosphorylation is inhibited by GNE-9605 (10 and 50 mg/kg; ip; once) in BAC transgenic mice that express human LRRK2 protein[1]. In the biochemical assay, GNE-9605 (1 mg/kg, po; 0.5 mg/kg, iv; once) exhibits LRRK2 Ki of 2 nM and a cellular IC50 of 19 nM. GNE-9605 has exceptional oral bioavailability and total plasma clearance [1]. | |
| Animal Protocol |
Animal/Disease Models: BAC transgenic mice expressing human LRRK2 protein[1] . Doses: 10 and 50 mg/kg Route of Administration: intraperitoneal (ip)injection; once Experimental Results: Inhibited LRRK2 Ser1292 autophosphorylation in a dose-dependent manner. Animal/Disease Models: BAC transgenic mice expressing human LRRK2 protein[1]. Doses: 1 mg/kg, po ; 0.5 mg/kg, iv Route of Administration: Oral administration and intravenous (iv) injection; once Experimental Results: Demonstrated a total plasma clearance of 26 mL min-1 kg-1 with excellent oral bioavailability (90%). |
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| References |
[1]. Discovery of highly potent, selective, and brain-penetrant aminopyrazole leucine-rich repeat kinase 2 (LRRK2) small molecule inhibitors. J Med Chem. 2014 Feb 13;57(3):921-36. [2]. Exploring the focal role of LRRK2 kinase in Parkinson's disease. Environ Sci Pollut Res Int. 2022 May;29(22):32368-32382. |
Solubility Data
| Solubility (In Vitro) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (4.62 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 20.8 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: ≥ 2.08 mg/mL (4.62 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 20.8 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. Solubility in Formulation 3: ≥ 2.08 mg/mL (4.62 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 20.8 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 | 2.2231 mL | 11.1153 mL | 22.2306 mL | |
| 5 mM | 0.4446 mL | 2.2231 mL | 4.4461 mL | |
| 10 mM | 0.2223 mL | 1.1115 mL | 2.2231 mL |