JH-II-127
JH-II-127 Basic information
- Product Name:
- JH-II-127
- Synonyms:
-
- JH-II-127
- (4-((5-Chloro-4-(methylamino)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)-3-methoxyphenyl)(morpholi
- (4-((5-chloro-4-(methylamino)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)-3-methoxyphenyl)(morpholino)methanone
- 2-anilino-4-methylamino-5-chloropyrrolopyrimidine
- 2-ANILINO-4-METHYLAMINO-5-CHLOROPYRROLOPYRIMIDINE;JH-II127;JH-II 127
- [4-[[5-Chloro-4-(methylamino)-7H-pyrrolo[2,3-d]pyrimidin-2-yl]amino]-3-methoxyphenyl]-4-morpholinyl-methanone
- Methanone, [4-[[5-chloro-4-(methylamino)-7H-pyrrolo[2,3-d]pyrimidin-2-yl]amino]-3-methoxyphenyl]-4-morpholinyl-
- [4-[[5-chloro-4-(methylamino)-7H-pyrrolo[2,3-d]pyrimidin-2-yl]amino]-3-methoxyphenyl]-morpholin-4-ylmethanone
- CAS:
- 1700693-08-8
- MF:
- C19H21ClN6O3
- MW:
- 416.86
- Mol File:
- 1700693-08-8.mol
JH-II-127 Chemical Properties
- Melting point:
- >166°C (dec.)
- Density
- 1.458±0.06 g/cm3(Predicted)
- storage temp.
- Refrigerator
- solubility
- DMSO (Slightly), Methanol (Slightly)
- pka
- 12.49±0.50(Predicted)
- form
- Solid
- color
- White to Pale Beige
- 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)
- InChIKey
- HUEKBQXFNHWTQQ-UHFFFAOYSA-N
- SMILES
- Clc1c2c(nc([nH]c2NC)Nc3c(cc(cc3)C(=O)N4CCOCC4)OC)nc1
JH-II-127 Usage And Synthesis
Description
JH-II-127 is an orally bioavailable inhibitor of wild-type (WT) and mutant forms of leucine-rich repeat kinase 2 (LRRK2). It inhibits WT LRRK2, as well as LRRK2 containing the G2019S and A2016T substitution mutations (IC50s = 6.6, 2.2, and 47.7 nM, respectively), which are present in certain patients with Parkinson’s disease, but not LRRK2 containing both mutations (IC50 = 3,080 nM). JH-II-127 (0.1-0.3 μM) inhibits phosphorylation of the serines at positions 910 and 935 of WT LRRK2 and LRRK2G2019S in vitro. It also inhibits Ser935 phosphorylation in vivo in mouse brain, spleen, and kidney when administered at a dose of 30 mg/kg.
Uses
JH-II-127 is a highly potent, selective, and brain penetrant LRRK2 inhibitor.
in vivo
JH-II-127 (100 mg/kg; i.p.; single) results in near complete dephosphorylation of Ser935 of LRRK2 in all tissues including brain[1].
| matrix | route | Tmax (h) | C0/Cmax (ng/mL) | AUCLast (hng/mL) | AUGINF (hng/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 | 135.24 | 1.7 |
| brain | PO (10 mg/kg) | 1 | 247.35 | 688.21 | 762.38 | - | - | - |
| Animal Model: | Wild type male C57BL/6 mice[1]. |
| Dosage: | 2 mg/kg (for i.v.); 10 mg/kg (for p.o.); 10, 30, 100 mg/kg (for i.p.) |
| Administration: | Intravenous and intraperitoneal injection; oral administration; single. |
| Result: | Led to near complete dephosphorylation of Ser935 of LRRK2 in all tissues including brain when at 100 mg/kg of i.p. and near complete inhibition in all tissues at 30 mg/kg but only partial inhibition in brain at the 10 mg/kg dose. Demonstrated good oral bioavailability. |
storage
Store at -20°C
References
[1] JOHN M. HATCHER. Discovery of a Pyrrolopyrimidine (JH-II-127), a Highly Potent, Selective, and Brain Penetrant LRRK2 Inhibitor[J]. ACS Medicinal Chemistry Letters, 2015, 6 5: 584-589. DOI: 10.1021/acsmedchemlett.5b00064
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