HG-10-102-01 is an inhibitor of leucine-rich repeat kinase 2 (LRRK2; IC50 = 20.3 nM). It also inhibits the G2019S, A2016T, and [G2019S+A2016T] mutants of LRRK2 (IC50s = 3.2, 153, and 95.9 nM, respectively). HG-10-102-01 substantially inhibits Ser910 and Ser935 phosphorylation of both wild-type and G2019S mutant LRRK2 in cells. When given intraperitoneally, HG-10-102-01 penetrates the blood-brain barrier and inhibits phosphorylation of LRRK2 in the brain as well as the kidney and spleen.
[4-[[5-Chloro-4-(methylamino)-2-pyrimidinyl]amino]-3-methoxyphenyl]-4-morpholinylmethanone is an aminopyrimidine derivative as LRRK2 modulators used for the treatment of Parkinson''s disease.
ChEBI: 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.
HG-10-102-01 (0-100 mg/kg, IP, once) shows inhibition of LRRK2 Ser910/Ser935 phosphorylation in kidney, spleen, and brain of mice[1].
HG-10-102-01 (1 mg/kg, IV; 10 mg/kg, PO; once) shows good oral bioavailability (%F = 67), a short half-life of 0.13 h, and low plasma exposure[1].
| Animal Model: | Wild type male C57BL/6 mice[1] |
| Dosage: | 0, 3, 10, 30, 50, and 100 mg/kg |
| Administration: | IP, once |
| Result: | Showed near complete dephosphorylation of Ser910 and Ser935 of LRRK2 in all tissues including brain at 100 mg/kg and 50 mg/kg, but only partial inhibition in brain at the 30 and 10 mg/kg doses. |
| Animal Model: | Wild type male C57BL/6 mice[1] |
| Dosage: | 1 mg/kg (IV); 10 mg/kg (PO) |
| Administration: | IV, PO; once (Pharmacokinetic Analysis) |
| Result: | Pharmacokinetic Parameters of HG-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/mLh) | 74.85 | 502.34 | | AUCINF (ng/mLh) | 75.06 | 503.41 | | T1/2 (h) | 0.13 | | | CL (mL/min/kg) | 222.04 | | | Vss (L/kg) | 1.68 | | | F (%) | | 67 |
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[1] choi hg1, zhang j, deng x, hatcher jm, patricelli mp, zhao z, alessi dr, gray ns. brain penetrant lrrk2 inhibitor. acs med chem lett. 2012 aug 9;3(8):658-662. epub 2012 jun 18.
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