GSK163090 is novel, potent, selective, and orally bioavailable antagonist of the 5-HT1A/B/D receptor that has the potential to be used as a fast-onset antidepressant/anxiolytic. It displayed strong affinities across the 5-HT1A, 5-HT1B, and 5-HT1D receptors, low intrinsic activities, and strong selectivity against the serotonin transporter. Due to the combination of strong preclinical developability profile and potent in vivo activity, GSK163090 was chosen as a drug candidate with the intention of evaluating its potential as a quick-acting antidepressant/anxiolytic.

Physicochemical Properties

Molecular Formula	C25H29N5O
Molecular Weight	415.53
Exact Mass	415.237
Elemental Analysis	C, 72.26; H, 7.03; N, 16.85; O, 3.85
CAS #	844903-58-8
Related CAS #	844903-58-8; 844903-52-2(HCl)
PubChem CID	11292933
Appearance	Solid powder
Density	1.2±0.1 g/cm3
Index of Refraction	1.644
LogP	2.35
Hydrogen Bond Donor Count	1
Hydrogen Bond Acceptor Count	4
Rotatable Bond Count	5
Heavy Atom Count	31
Complexity	607
Defined Atom Stereocenter Count	0
SMILES	O=C1N(C2C=C(CCN3CCN(C4C5C(=NC(C)=CC=5)C=CC=4)CC3)C=CC=2)CCN1
InChi Key	ANGUXJDGJCHGOG-UHFFFAOYSA-N
InChi Code	InChI=1S/C25H29N5O/c1-19-8-9-22-23(27-19)6-3-7-24(22)29-16-14-28(15-17-29)12-10-20-4-2-5-21(18-20)30-13-11-26-25(30)31/h2-9,18H,10-17H2,1H3,(H,26,31)
Chemical Name	1-[3-[2-[4-(2-methylquinolin-5-yl)piperazin-1-yl]ethyl]phenyl]imidazolidin-2-one
Synonyms	GSK163090; GSK-163090; GSK 163090
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

Targets	5-HT1A Receptor ( pKi = 9.4 nM ); 5-HT1B Receptor ( pKi = 8.5 nM ); 5-HT1D Receptor ( pKi = 9.7 nM ); D2 Receptor ( pKi = 6.3 nM ); D3 Receptor ( pKi = 6.7 nM ); 5-HT2A Receptor ( pKi = 6 nM ); 5-HT2B Receptor ( pKi = 6.3 nM ); 5-HT2C Receptor ( pKi = 5.8 nM ); Human 5-HT6 Receptor ( pKi < 5.3 nM ); Human 5-HT7 Receptor ( pKi = 6.8 nM )
ln Vitro	In vitro activity: GSK163090 (compound 36) shows a moderate functional antagonism (pIC50=6.9) against the contraction of the rabbit aorta induced by phenylephrine, but no agonist activity at R1 receptors[1]. GSK163090 is a moderate P-glycoprotein (P-gp) substrate (BA/AB = 2.8) at 1 μM concentration, according to the ratio of apparent permeabilities measured from basolateral-to-apical (BA) to apical-to-basolateral (AB)[1].
ln Vivo	GSK163090 (compound 36) treatment clearly inhibits the 8-OH-DPAT-induced hyperlocomotor activity (hLMA) in male Sprague-Dawley rats in a dose-dependent manner, with ED50 values ranging from 0.03 to 1 mg/kg[1].
Animal Protocol
References	[1]. Discovery of 1-(3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)-2-imidazolidinone (GSK163090), a Potent, selective, and orally active 5-HT1A/B/D receptor antagonist. J Med Chem. 2010 Dec 9;53(23):8228-8240.

Solubility Data

Solubility (In Vitro)

DMSO: ~14.3 mg/mL (~34.4 mM) Water: <1 mg/mL Ethanol: <1 mg/mL

Solubility (In Vivo)

Solubility in Formulation 1: ≥ 1.43 mg/mL (3.44 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 14.3 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: ≥ 1.43 mg/mL (3.44 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 14.3 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: ≥ 1.43 mg/mL (3.44 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 14.3 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	2.4066 mL	12.0328 mL	24.0657 mL
	5 mM	0.4813 mL	2.4066 mL	4.8131 mL
	10 mM	0.2407 mL	1.2033 mL	2.4066 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.