Tyk2-IN-5 (compound 6) is a potent, selective and orally bioactive tyrosine kinase 2 (Tyk2) inhibitor that works on the JH2 domain. The Ki of Tyk2-IN-5 for Tyk2 JH2 is 0.086 nM and the IC50 for IFNα is 25 nM. Tyk2-IN-5 can efficiently inhibit the production of IFNγ in pharmacodynamic rat models and has complete efficacy in rat arthritis models.

Physicochemical Properties

Molecular Formula	C21H19FN8O2
Molecular Weight	434.426366090775
Exact Mass	434.161
CAS #	1797432-62-2
PubChem CID	91809175
Appearance	Light yellow to yellow solid powder
LogP	1.9
Hydrogen Bond Donor Count	3
Hydrogen Bond Acceptor Count	8
Rotatable Bond Count	6
Heavy Atom Count	32
Complexity	807
Defined Atom Stereocenter Count	2
SMILES	F[C@H]1C[C@H]1NC(C1=CN=C2C(=CC(NC3=CC=CN(C4C=CC=CN=4)C3=O)=NN12)NC)=O
InChi Key	YITUGUNLCGLOII-GXTWGEPZSA-N
InChi Code	InChI=1S/C21H19FN8O2/c1-23-15-10-17(26-13-5-4-8-29(21(13)32)18-6-2-3-7-24-18)28-30-16(11-25-19(15)30)20(31)27-14-9-12(14)22/h2-8,10-12,14,23H,9H2,1H3,(H,26,28)(H,27,31)/t12-,14+/m0/s1
Chemical Name	N-[(1R,2S)-2-fluorocyclopropyl]-8-(methylamino)-6-[(2-oxo-1-pyridin-2-ylpyridin-3-yl)amino]imidazo[1,2-b]pyridazine-3-carboxamide
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	Tyk2-IN-5 exhibits Jak1-3-dependent cellular activity with an IC50 of >12.5 μM and inhibits Jak1-3 with an IC50 value of >2 μM [1].
ln Vivo	In adjuvant arthritis models, Tyk2-IN-5 (5, 10 mg/kg; face; twice daily for 20 days) exhibits high efficacy [1]. In a dose-dependent manner, Tyk2-IN-5 (1, 10 mg/kg; basalt) suppresses the generation of IFNγ produced by IL-12/IL-18 [1]. One dose of Tyk2-IN-5 (10 mg/kg; dam) has been recorded in the
Animal Protocol	Animal/Disease Models: Lewis male rat (IL-12/IL-18 induced) [1]. Doses: 1, 10 mg/kg Route of Administration: Oral; Single Experimental Results:IL-12/IL-18-induced IFNγ production was inhibited by 45% and 77% at doses of 1 and 10 mg/kg, respectively. Animal/Disease Models: Lewis male rat, mouse [1]. Doses: 10 mg/kg Route of Administration: po (po (oral gavage)) Single Experimental Results:1.19 pharmacokinetic/PK/PK parameters of Tyk2-IN-5 in mice and rats [1]. PO (10 mg/kg) Mouse Rat Cmax (μM) 15 9.4 AUC0-24 (μM·h) 19 57 CL (mL/min/kg) 16 7.8 F (%) 86 114
References	[1]. Identification of Imidazo[1,2-b]pyridazine Derivatives as Potent, Selective, and Orally Active Tyk2 JH2 Inhibitors. ACS Med Chem Lett. 2019 Feb 21;10(3):383-388.

Solubility Data

Solubility (In Vitro)

DMSO : ~43.33 mg/mL (~99.74 mM)

Solubility (In Vivo)

Solubility in Formulation 1: ≥ 2.17 mg/mL (5.00 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 21.7 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	2.3019 mL	11.5093 mL	23.0187 mL
	5 mM	0.4604 mL	2.3019 mL	4.6037 mL
	10 mM	0.2302 mL	1.1509 mL	2.3019 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.