RO 46-8443 is a novel, potent, selective and non-peptidic antagonist of the endothelin ETB receptor. RO 46-8443 demonstrates a selectivity of up to 2000 times for ETB receptors in terms of both functional inhibition and binding inhibitory potency. Ro 46-8443 reduced blood pressure in normotensive rats, but it created a pressor effect in SHR and DOCA rats because it blocked the ETB-mediated release of nitric oxide, which was inhibited by L-NAME. In rats treated with chronic L-NAME to hypertension, Ro 46-8443 had a depressor effect rather than a pressor effect. Therefore, Ro 46-8443 indicates that endothelial "vasorelaxant" ETB receptors have a predominant influence in DOCA rats and SHR, whereas in normotensive rats, ETB receptors appear to have a predominant role in mediating a vasoconstrictor tone.

Physicochemical Properties

Molecular Formula	C31H35N3O8S
Molecular Weight	609.69
Exact Mass	609.214
Elemental Analysis	C, 61.07; H, 5.79; N, 6.89; O, 20.99; S, 5.26
CAS #	175556-12-4
Related CAS #	175556-12-4
PubChem CID	5312146
Appearance	White to off-white solid powder
Density	1.3±0.1 g/cm3
Boiling Point	683.1±65.0 °C at 760 mmHg
Flash Point	367.0±34.3 °C
Vapour Pressure	0.0±2.2 mmHg at 25°C
Index of Refraction	1.602
LogP	3.22
Hydrogen Bond Donor Count	3
Hydrogen Bond Acceptor Count	11
Rotatable Bond Count	13
Heavy Atom Count	43
Complexity	928
Defined Atom Stereocenter Count	1
SMILES	S(C1C([H])=C([H])C(=C([H])C=1[H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H])(N([H])C1=C(C(=NC(C2C([H])=C([H])C(=C([H])C=2[H])OC([H])([H])[H])=N1)OC([H])([H])C([H])(C([H])([H])O[H])O[H])OC1=C([H])C([H])=C([H])C([H])=C1OC([H])([H])[H])(=O)=O
InChi Key	DRIHNVYRUGBDHI-JOCHJYFZSA-N
InChi Code	InChI=1S/C31H35N3O8S/c1-31(2,3)21-12-16-24(17-13-21)43(37,38)34-29-27(42-26-9-7-6-8-25(26)40-5)30(41-19-22(36)18-35)33-28(32-29)20-10-14-23(39-4)15-11-20/h6-17,22,35-36H,18-19H2,1-5H3,(H,32,33,34)/t22-/m1/s1
Chemical Name	4-tert-butyl-N-[6-[(2R)-2,3-dihydroxypropoxy]-5-(2-methoxyphenoxy)-2-(4-methoxyphenyl)pyrimidin-4-yl]benzenesulfonamide
Synonyms	RO 468443; RO-468443; RO468443; RO 46,8443; RO-46,8443; RO46,8443; RO 46-8443; RO46-8443; RO-46-8443
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, 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

Targets	ETB ( IC50 = 34-69 nM ); ETA ( IC50 = 6800 nM )
References	[1]. In vitro characterisation of Ro 46-8443, the first non-peptide antagonist selective for the endothelin ETB receptor. FEBS Lett. 1996;383(1-2):37-41. [2]. The role of ETB receptors in normotensive and hypertensive rats as revealed by the non-peptide selective ETB receptor antagonist Ro 46-8443. FEBS Lett. 1996;383(1-2):42-45.

Solubility Data

Solubility (In Vitro)

DMSO: ~250 mg/mL (~410.0 mM) Water: N/A Ethanol: N/A

Solubility (In Vivo)

Solubility in Formulation 1: ≥ 2.08 mg/mL (3.41 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 2: 2.08 mg/mL (3.41 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication. 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. Solubility in Formulation 3: ≥ 2.08 mg/mL (3.41 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 20.8 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	1.6402 mL	8.2009 mL	16.4018 mL
	5 mM	0.3280 mL	1.6402 mL	3.2804 mL
	10 mM	0.1640 mL	0.8201 mL	1.6402 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.