BI 689648 is a novel, potent and highly selective aldosterone synthase (AS) inhibitor that can attenuate the production of aldosterone directly and has been proposed as an alternative to mineralocorticoid receptor antagonists for blocking the pathologic effects of excess aldosterone. It can inhibit CYP11B1 and CYP11B2 with IC50s of 310 and 2.1 nM, respectively. BI 689648 represents an important step forward toward developing ASIs with greater potential for clinical success in cardiometabolic diseases.

Physicochemical Properties

Molecular Formula	C16H18N4O2
Molecular Weight	298.339723110199
Exact Mass	298.142
CAS #	1633009-87-6
PubChem CID	86305663
Appearance	White to off-white solid powder
LogP	0.6
Hydrogen Bond Donor Count	1
Hydrogen Bond Acceptor Count	4
Rotatable Bond Count	3
Heavy Atom Count	22
Complexity	392
Defined Atom Stereocenter Count	0
SMILES	N1(C(N)=O)C2C(=CC(C3=CC(COC)=CN=C3)=CN=2)CCC1
InChi Key	DJFDCVNQDFICKV-UHFFFAOYSA-N
InChi Code	InChI=1S/C16H18N4O2/c1-22-10-11-5-13(8-18-7-11)14-6-12-3-2-4-20(16(17)21)15(12)19-9-14/h5-9H,2-4,10H2,1H3,(H2,17,21)
Chemical Name	6-(5-(methoxymethyl)pyridin-3-yl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide
Synonyms	BI 689648; BI-689648; BI689648.
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	BI 689648 has significant selectivity in vitro when compared to FAD and LCI699; its IC50 for CYP11B2 is 2.1 nM, and its selectivity factor is 149 higher than that of CYP11B1. Comparatively, FAD286 shows an IC50 against CYP11B2 that is comparable to that of BI 689648 (2.5 nM); but, due to its increased efficacy against CYP11B1 (94 nM), it has a comparatively small selectivity factor of 38, which is about 4-fold lower [1].
ln Vivo	Following oral treatment to cynomolgus monkeys, peak plasma concentrations of BI 689648 (5 mg/kg) are approximately 500 nM. For BI 689648 (aldosterone EC50=2 nM), substantial increases in 11-DOC were only seen at plasma concentrations >2000 nM or aldosterone EC50 >1000-fold, whereas FAD286 demonstrated a ~100-fold window. BI 689648 has modest effects on 11-DC and only at very high plasma concentrations (~10 μM) [1].
References	[1]. Selectivity of BI 689648, a Novel, Highly Selective Aldosterone Synthase Inhibitor: Comparison with FAD286 and LCI699 in Nonhuman Primates. J Pharmacol Exp Ther. 2016 Oct;359(1):142-50.

Solubility Data

Solubility (In Vitro)

DMSO : ~30 mg/mL (~100.56 mM)

Solubility (In Vivo)

Solubility in Formulation 1: ≥ 2.5 mg/mL (8.38 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 25.0 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: ≥ 2.5 mg/mL (8.38 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 25.0 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: ≥ 2.5 mg/mL (8.38 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 25.0 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	3.3519 mL	16.7594 mL	33.5188 mL
	5 mM	0.6704 mL	3.3519 mL	6.7038 mL
	10 mM	0.3352 mL	1.6759 mL	3.3519 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.