GW766994 (GW-766994) is a novel, potent, specific and orally bioavailable small molecule antagonist of the CCR3 (chemokine receptor-3) receptor. It is being investigated in clinical trial for asthma and eosinophilic bronchitis. In a double-blind parallel group study, 60 patients with asthma were randomized to 300 mg of GW766994 twice daily or matching placebo for 10 days followed by prednisone 30 mg for 5 days. Of these patients, 53 had a sputum eosinophil count > 4.9% at baseline. Despite plasma concentrations of drug consistent with > 90% receptor occupancy during the dosing period, the CCR3 antagonist did not significantly reduce eosinophils or eosinophil progenitor cells (CD34(+) 45(+) IL-5Rα(+)) in sputum or in blood. The ex vivo chemotactic effect of sputum supernatants on eosinophils was attenuated by GW766944 compared to placebo. There was no improvement in FEV1 ; however, there was a modest but statistically significant improvement in PC20 methacholine (0.66 doubling dose) and ACQ scores, (0.43). Whilst the improvement in PC20 is statistically significant, it is not of clinical significance.

Physicochemical Properties

Molecular Formula	C21H24CL2N4O3
Molecular Weight	451.346262931824
Exact Mass	450.122
CAS #	408303-43-5
PubChem CID	10218765
Appearance	Light yellow to yellow solid powder
Density	1.3±0.1 g/cm3
Boiling Point	685.8±55.0 °C at 760 mmHg
Flash Point	368.5±31.5 °C
Vapour Pressure	0.0±2.1 mmHg at 25°C
Index of Refraction	1.608
LogP	1.5
Hydrogen Bond Donor Count	3
Hydrogen Bond Acceptor Count	4
Rotatable Bond Count	7
Heavy Atom Count	30
Complexity	575
Defined Atom Stereocenter Count	1
SMILES	C1CO[C@H](CN1CC2=CC(=C(C=C2)Cl)Cl)CNC(=O)NCC3=CC=C(C=C3)C(=O)N
InChi Key	GPLUUMAKBFSDIE-KRWDZBQOSA-N
InChi Code	InChI=1S/C21H24Cl2N4O3/c22-18-6-3-15(9-19(18)23)12-27-7-8-30-17(13-27)11-26-21(29)25-10-14-1-4-16(5-2-14)20(24)28/h1-6,9,17H,7-8,10-13H2,(H2,24,28)(H2,25,26,29)/t17-/m0/s1
Chemical Name	4-[[[(2S)-4-[(3,4-dichlorophenyl)methyl]morpholin-2-yl]methylcarbamoylamino]methyl]benzamide
Synonyms	GW-766994; GW-994; GW766994; GW994; GW 766994; GW 994
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	GW 766994 is an antagonist of chemokine receptor 3 (CCR3) that started eosinophilic kinase clinical trials [1]. In hippocampal neurons, GW 766994 (10 μM) reverses CCL11-induced increases in GSK3β, tau phosphorylation, CDK5 activation, and CDK5 phosphorylation [2].
References	[1]. Safety and efficacy of an oral CCR3 antagonist in patients with asthma and eosinophilic bronchitis: a randomized, placebo-controlled clinical trial. Clin Exp Allergy. 2014 Apr;44(4):508-16. [2]. Targeting CCR3 to Reduce Amyloid-β Production, Tau Hyperphosphorylation, and Synaptic Loss in a Mouse Model of Alzheimer's Disease. Mol Neurobiol. 2017 Dec;54(10):7964-7978.

Solubility Data

Solubility (In Vitro)

DMSO : ~56 mg/mL (~124.07 mM)

Solubility (In Vivo)

Solubility in Formulation 1: ≥ 2.33 mg/mL (5.16 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 23.3 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: ≥ 2.33 mg/mL (5.16 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 23.3 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: ≥ 2.33 mg/mL (5.16 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 23.3 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	2.2156 mL	11.0779 mL	22.1558 mL
	5 mM	0.4431 mL	2.2156 mL	4.4312 mL
	10 mM	0.2216 mL	1.1078 mL	2.2156 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.