ELN441958 (ELN-441958) is a novel, potent, and small molecule antagonist of neutral bradykinin B1 receptor which inhibits the binding of the B1 agonist ligand [3H]DAKD to IMR-90 cells with Ki of 0.26 nM. ELN441958 shows significant systemic efficacy and high oral bioavailability in treating inflammatory pain in rhesus monkeys. Though species-dependent potency differences, metabolic instability, and low oral exposure of current agents have hindered efforts to demonstrate efficacy of receptor antagonists, the bradykinin B(1) receptor plays a critical role in chronic pain and inflammation.
Physicochemical Properties
| Molecular Formula | C29H29CLN4O2 |
| Molecular Weight | 501.01916 |
| Exact Mass | 500.198 |
| Elemental Analysis | C, 69.52; H, 5.83; Cl, 7.08; N, 11.18; O, 6.39 |
| CAS # | 913064-47-8 |
| Related CAS # | 913064-47-8 |
| PubChem CID | 11848206 |
| Appearance | White to off-white solid powder |
| LogP | 5.486 |
| Hydrogen Bond Donor Count | 0 |
| Hydrogen Bond Acceptor Count | 4 |
| Rotatable Bond Count | 3 |
| Heavy Atom Count | 36 |
| Complexity | 799 |
| Defined Atom Stereocenter Count | 0 |
| SMILES | O=C(N1CCC2(CCN(C3C=CN=CC=3)CC2)CC1)C1C=C(N2CC3C(=C(C=CC=3)Cl)C2=O)C=CC=1 |
| InChi Key | ARYQHSWJGHCGJS-UHFFFAOYSA-N |
| InChi Code | InChI=1S/C29H29ClN4O2/c30-25-6-2-4-22-20-34(28(36)26(22)25)24-5-1-3-21(19-24)27(35)33-17-11-29(12-18-33)9-15-32(16-10-29)23-7-13-31-14-8-23/h1-8,13-14,19H,9-12,15-18,20H2 |
| Chemical Name | 7-chloro-2-[3-(9-pyridin-4-yl-3,9-diazaspiro[5.5]undecane-3-carbonyl)phenyl]-3H-isoindol-1-one |
| Synonyms | ELN-441958; ELN441958; ELN 441958 |
| 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 | native human bradykinin B1 receptor ( Ki = 0.26 nM ) |
| ln Vitro |
ELN-441958 exhibits primate selectivity over rodent B1 receptors, possessing a human rank order potency (KB, nanomolar) of 0.12 ± 0.02. Rat (1.5 ± 0.4) < mouse (14 ± 4) > rhesus monkey (0.24 ± 0.01)[1]. ELN-441958 exhibits excellent metabolic stability and permeability[1]. |
| ln Vivo |
ELN-441958 (1–10 mg/kg; s.c.; once) dose-dependently reduces carrageenan-induced thermal hyperalgesia in a rhesus monkey tail-withdrawal model[1]. ELN-441958 (0–10 mg/kg; i.v. or p.o.) shows a good pharmacokinetic profile in the rat and rhesus monkey[1]. |
| Animal Protocol |
Adult male and female rhesus monkeys 1, 3, or 10 mg/kg Subcutaneous injection, 30 min before carrageenan injection |
| References |
[1]. Pharmacological, pharmacokinetic, and primate analgesic efficacy profile of the novel bradykinin B1 Receptor antagonist ELN441958. J Pharmacol Exp Ther.2007 Aug;322(2):619-630. |
Solubility Data
| Solubility (In Vitro) | DMSO: 50~100 mg/mL (99.8~199.6 mM) |
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (4.99 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 (4.99 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 (4.99 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 | 1.9959 mL | 9.9796 mL | 19.9593 mL | |
| 5 mM | 0.3992 mL | 1.9959 mL | 3.9919 mL | |
| 10 mM | 0.1996 mL | 0.9980 mL | 1.9959 mL |