CZC-54252 is a potent, selective, and metabolically stable LRRK2 inhibitor (Leucine-rich repeat kinase-2) with IC50 of 1.28 nM and 1.85 nM for wild-type and G2019S LRRK2 respectively. CZC-25146 prevents mutant LRRK2-induced injury of cultured rodent and human neurons with mid-nanomolar potency. CZC-54252 inhibited the activity of recombinant human wild-type LRRK2 with an IC50 ranging from 1 to 5 nM. The G2019S mutant was inhibited with an IC50 ranging from ～2 to ～7 nM in a TF-FRET assay. In addition, they were screened against a kinase panel of 185 kinases and exhibited good selectivity. CZC-25146 (19) inhibited five other kinases, PLK4, GAK, TNK1, CAMKK2, and PIP4K2C, with high potency only, but none of them have been classified as predictors of genotoxicity or hematopoietic toxicity.

Physicochemical Properties

Molecular Formula	C22H25CLN6O4S
Molecular Weight	504.99
Exact Mass	504.134
CAS #	1191911-27-9
Related CAS #	CZC-54252 hydrochloride;1784253-05-9
PubChem CID	44252734
Appearance	White to off-white solid powder
Density	1.5±0.1 g/cm3
Boiling Point	718.1±70.0 °C at 760 mmHg
Flash Point	388.1±35.7 °C
Vapour Pressure	0.0±2.3 mmHg at 25°C
Index of Refraction	1.667
LogP	1.67
Hydrogen Bond Donor Count	3
Hydrogen Bond Acceptor Count	10
Rotatable Bond Count	8
Heavy Atom Count	34
Complexity	737
Defined Atom Stereocenter Count	0
InChi Key	CLGWUCNXOBLWFM-UHFFFAOYSA-N
InChi Code	InChI=1S/C22H25ClN6O4S/c1-32-20-13-15(29-9-11-33-12-10-29)7-8-19(20)26-22-24-14-16(23)21(27-22)25-17-5-3-4-6-18(17)28-34(2,30)31/h3-8,13-14,28H,9-12H2,1-2H3,(H2,24,25,26,27)
Chemical Name	N-[2-[[5-chloro-2-(2-methoxy-4-morpholin-4-ylanilino)pyrimidin-4-yl]amino]phenyl]methanesulfonamide
Synonyms	CZC-54252; CZC 54252; CZC54252
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)

Biological Activity

ln Vitro	The recombinant human wild-type LRRK2 is inhibited by CZC-54252, with an IC50 ranging from approximately 1 to approximately 5 nM. They also demonstrated good selectivity when tested against a kinome of 185 kinases [1]. At 1.6 nM, CZC-54252 fully restored human neuronal damage to wild-type levels after attenuating G2019S LRRK2-induced neuronal damage with an EC50 of less than 1 nM [1].
ln Vivo	In vivo pharmacology established a volume of distribution of 5.4 L/kg and a clearance of 2.3 L/h/kg for CZC-25146 (19). Unfortunately, it exhibited a poor brain penetration of just 4%..
Animal Protocol	Mice
References	[1]. Chemoproteomics-based design of potent LRRK2-selective lead compounds that attenuate Parkinson's disease-related toxicity in human neurons. ACS Chem Biol. 2011 Oct 21;6(10):1021-8.
Additional Infomation	CZC-25146 is a member of the class of aminopyrimidines that is 2,6-diamino-5-chloropyrimidine in which the amino groups at positions 2 and 6 are respectively carrying 2-methoxy-4-(morpholin-4-yl)phenyl and 2-(methanesulfonylamino)phenyl substituents. It is an inhibitor of the Parkinson's disease kinase 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, an aromatic ether, an organochlorine compound, a sulfonamide and a secondary amino compound.

Solubility Data

Solubility (In Vitro)

DMSO:21 mg/mL Water:<1 mg/mL Ethanol:

Solubility (In Vivo)

Solubility in Formulation 1: ≥ 2.5 mg/mL (4.95 mM) (saturation unknown) in 10% DMSO + 40% PEG300 +5% Tween-80 + 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 25.0 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.  (Please use freshly prepared in vivo formulations for optimal results.)

Preparing Stock Solutions		1 mg	5 mg	10 mg
	1 mM	1.9802 mL	9.9012 mL	19.8024 mL
	5 mM	0.3960 mL	1.9802 mL	3.9605 mL
	10 mM	0.1980 mL	0.9901 mL	1.9802 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.