PKC-theta inhibitor is a novel, potent and selective PKC-θ inhibitor with an IC50 of 12 nM. It was discovered from an uHTS campaign to identify selective inhibitors of PKC-theta. Initial triaging of the hit set based on selectivity and historical analysis led to the identification of 2,4-diamino-5-nitropyrimidines as potent and selective PKC-theta inhibitors. A homology model and initial SAR is presented demonstrating that a 2-arylalkylamino substituent in conjunction with suitable 4-diamino substituent are essential for achieving selectivity over many kinases. Additional hit to lead profiling is presented on selected compounds.

Physicochemical Properties

Molecular Formula	C20H25F3N6O3
Molecular Weight	454.45
Exact Mass	454.194
CAS #	736048-65-0
Related CAS #	736048-65-0
PubChem CID	10253430
Appearance	White to off-white solid powder
LogP	4.7
Hydrogen Bond Donor Count	3
Hydrogen Bond Acceptor Count	11
Rotatable Bond Count	8
Heavy Atom Count	32
Complexity	586
Defined Atom Stereocenter Count	0
SMILES	C1CC(CN)CCC1CNC1=NC(NCC2=C(C=CC=C2)OC(F)(F)F)=NC=C1[N+](=O)[O-]
InChi Key	HKOWATVSFKRXRW-UHFFFAOYSA-N
InChi Code	InChI=1S/C20H25F3N6O3/c21-20(22,23)32-17-4-2-1-3-15(17)11-26-19-27-12-16(29(30)31)18(28-19)25-10-14-7-5-13(9-24)6-8-14/h1-4,12-14H,5-11,24H2,(H2,25,26,27,28)
Chemical Name	N4-((4-(aminomethyl)cyclohexyl)methyl)-5-nitro-N2-(2-(trifluoromethoxy)benzyl)pyrimidine-2,4-diamine
Synonyms	PKC-theta inhibitor;PKC-θ inhibitor;PKC theta inhibitor;PKC θ inhibitor;
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

References

[1]. Discovery of potent and selective PKC-theta inhibitors. Bioorg Med Chem Lett. 2007 Jan 1;17(1):225-30.

Solubility Data

Solubility (In Vitro)

DMSO:≥ 60mg/mL Water:N/A Ethanol:N/A

Solubility (In Vivo)

Solubility in Formulation 1: ≥ 2.5 mg/mL (5.50 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 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. Solubility in Formulation 2: ≥ 2.5 mg/mL (5.50 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 25.0 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. Solubility in Formulation 3: ≥ 2.5 mg/mL (5.50 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 25.0 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	2.2005 mL	11.0023 mL	22.0046 mL
	5 mM	0.4401 mL	2.2005 mL	4.4009 mL
	10 mM	0.2200 mL	1.1002 mL	2.2005 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.