GSK356278 is a potent, selective, orally bioactive and BBB (blood-brain barrier) permeable/penetrable phosphodiesterase 4 (PDE4) inhibitor (antagonist) with pIC50s of 8.6, 8.8 and 8.7 for human PDE4A, PDE4B and PDE4D, respectively. GSK356278 has anti~inflammatory activity and has anxiolytic (anti-anxiety) and cognitive-enhancing effects.

Physicochemical Properties

Molecular Formula	C21H25N7O2S
Molecular Weight	439.53
Exact Mass	439.179
CAS #	720704-34-7
PubChem CID	10252640
Appearance	White to off-white solid powder
LogP	3.829
Hydrogen Bond Donor Count	1
Hydrogen Bond Acceptor Count	9
Rotatable Bond Count	6
Heavy Atom Count	31
Complexity	598
Defined Atom Stereocenter Count	0
InChi Key	AWDJJMXJUOHGLC-UHFFFAOYSA-N
InChi Code	InChI=1S/C21H25N7O2S/c1-4-28-20-15(11-23-28)19(25-14-5-7-29-8-6-14)16(10-22-20)21-27-26-18(30-21)9-17-12(2)24-13(3)31-17/h10-11,14H,4-9H2,1-3H3,(H,22,25)
Chemical Name	5-[5-[(2,4-dimethyl-1,3-thiazol-5-yl)methyl]-1,3,4-oxadiazol-2-yl]-1-ethyl-N-(oxan-4-yl)pyrazolo[3,4-b]pyridin-4-amine
Synonyms	GSK 356278; GSK356278; GSK-356278
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 Note: Please store this product in a sealed and protected environment (e.g. under nitrogen), avoid exposure to moisture.
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	In a competitive filter binding assay using recombinant human PDE4B2B, GSK356278 rivals the enzyme [3H]rolipram expressed in yeast membranes for the high-affinity rolipram binding site (HARBS), with a pKi of 8.6 [1]. HARBS binding has pKi values of 7.9, 7.8, 8.4 and 8.5 in mice, marmosets and ferrets, respectively [1]. With a pIC50 of 7.6, GSK356278 inhibits the release of TNF-α in human whole blood when exposed to LPS[1].
ln Vivo	In chewing animals, GSK356278 (0.003-30 mg/kg; po) has anti-inflammatory efficacy without causing pica feeding [1]. In an anxiety model of nonhuman primates, GSK356278 (0.1-0.1 mg/kg; po) has been shown to be effective when exposure conditions do not cause vomiting [1]. Non-human primates that receive GSK356278 (4 dosages, 0.03, 0.1, 0.3, and 1.0 mg/kg for 6 weeks; po) perform better on the object search test [1]. Under an open source license, GSK356278 demonstrated bioavailability (gravity 91%, monkey 23%) and Cmax (gravity 205, monkey 41 nM) (gravity 1, monkey 0.2 mg/kg) [1].
Animal Protocol	Animal/Disease Models: Male Lewis rats (320-400 g) were treated with lipopolysaccharide (LPS) [1]. Doses: 0.003-3 mg/kg Route of Administration: Oral administration 30 minutes before LPS challenge Experimental Results: diminished neutrophil levels in a dose-dependent manner with an ED50 of 0.09 mg/kg. Animal/Disease Models: Male CD rat [1] Doses: 1 mg/kg (pharmacokinetic/PK/PK analysis) Route of Administration: intravenous (iv) (iv)injection and oral administration Experimental Results: Oral bioavailability (91%), Cmax (205 nM), T1/2 (2.2 h).
References	[1]. GSK356278, a potent, selective, brain-penetrant phosphodiesterase 4 inhibitor that demonstrates anxiolytic and cognition-enhancing effects without inducing side effects in preclinical species. J Pharmacol Exp Ther. 2014 Jul;350(1):153-63.
Additional Infomation	Gsk356278 has been used in trials studying the treatment and basic science of Anxiety Disorders, Huntington Disease, Depressive Disorder, Huntingtons Disease, and Depressive Disorder, Major, among others.

Solubility Data

Solubility (In Vitro)

DMSO : ~2.5 mg/mL (~5.69 mM)

Solubility (In Vivo)

Solubility in Formulation 1: ≥ 1.25 mg/mL (2.84 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 12.5 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: ≥ 1.25 mg/mL (2.84 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 12.5 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: ≥ 1.25 mg/mL (2.84 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 12.5 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	2.2752 mL	11.3758 mL	22.7516 mL
	5 mM	0.4550 mL	2.2752 mL	4.5503 mL
	10 mM	0.2275 mL	1.1376 mL	2.2752 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.