KDM5-IN-48 is a novel, potent, selective and orally bioavailable KDM5 inhibitor (IC50 o=15.1 nM). KDM5-IN-48 has improved cell potency (PC9 H3K4Me3 EC50=0.34μM). Furthermore, KDM5-IN-48 maintained suitable physiochemical properties and displayed an excellent pharmacokinetic (PK) profile in mice. When dosed orally in mice at 50mg/kg twice a day (BID), KDM5-IN-48 showed an unbound maximal plasma concentration (Cmax) >15-fold over its cell EC50, thereby providing a robust chemical probe for studying KDM5 biological functions in vivo.

Physicochemical Properties

Molecular Formula	C17H20N6O
Molecular Weight	324.3803
Exact Mass	324.169
CAS #	1628210-26-3
PubChem CID	118908379
Appearance	White to off-white solid powder
Density	1.3±0.1 g/cm3
Boiling Point	527.0±60.0 °C at 760 mmHg
Flash Point	272.5±32.9 °C
Vapour Pressure	0.0±1.4 mmHg at 25°C
Index of Refraction	1.659
LogP	1.64
Hydrogen Bond Donor Count	1
Hydrogen Bond Acceptor Count	5
Rotatable Bond Count	3
Heavy Atom Count	24
Complexity	715
Defined Atom Stereocenter Count	0
InChi Key	KRXWJZIHQRIGSJ-UHFFFAOYSA-N
InChi Code	InChI=1S/C17H20N6O/c1-10(2)13-14(12-8-19-22(9-12)17(3,4)5)21-15-11(6-18)7-20-23(15)16(13)24/h7-10,21H,1-5H3
Chemical Name	5-[1-(1,1-Dimethylethyl)-1H-pyrazol-4-yl]-4,7-dihydro-6-(1-methylethyl)-7-oxo-pyrazolo[1,5-a]pyrimidine-3-carbonitrile
Synonyms	KDM5-IN-48 KDM5 IN 48 KDM5IN48 KDM5 inhibitor-48 KDM5 inhibitor 48
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	KDM5B and KDM5C isoforms were shown to be potently inhibited by KDM5-IN-1 (IC50 values of 4.7 and 65.5 nM, respectively). Its impact on other KDM enzymes (1A, 2B, 3B, 4C, 5A, 6A, and 7B) is noticeably weaker. With an IC50 of 1.9 μM, it exhibits the largest inhibitory effect on KDM4C. Even so, KDM5-IN-1's selectivity for KDM4C is still more than 100 times greater than KDM5A's [1].
ln Vivo	KDM5-IN-1 demonstrated an unbound maximum plasma concentration Cmax >15 times its cellular EC50 when given orally to mice at a dose of 50 mg/kg twice daily, offering a strong platform for researching the in vivo biological functions of KDM5. chemical investigation tools[1].
References	[1]. Lead optimization of a pyrazolo[1,5-a]pyrimidin-7(4H)-one scaffold to identify potent, selective and orally bioavailable KDM5 inhibitors suitable for in vivo biological studies. Bioorg Med Chem Lett. 2016 Aug 15;26(16):4036-41.

Solubility Data

Solubility (In Vitro)

DMSO : ≥ 30 mg/mL (~92.48 mM)

Solubility (In Vivo)

Solubility in Formulation 1: ≥ 2.5 mg/mL (7.71 mM) (saturation unknown) in 5% DMSO + 40% PEG300 + 5% Tween80 + 50% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution. 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 (6.41 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 3: ≥ 2.08 mg/mL (6.41 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.  (Please use freshly prepared in vivo formulations for optimal results.)

Preparing Stock Solutions		1 mg	5 mg	10 mg
	1 mM	3.0828 mL	15.4140 mL	30.8280 mL
	5 mM	0.6166 mL	3.0828 mL	6.1656 mL
	10 mM	0.3083 mL	1.5414 mL	3.0828 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.