ELN 441958
ELN 441958 Basic information
- Product Name:
- ELN 441958
- Synonyms:
-
- 7-chloro-2-[3-(9-pyridin-4-yl-3,9-diazaspiro[5.5]undecane-3-carbonyl)phenyl]-3H-isoindol-1-one
- 7-Chloro-2-[3-[[9-(pyridin-4-yl)-3,9-diazaspiro[5.5]undecan-3-yl]carbonyl]phenyl]-2,3-dihydroisoindol-1-one
- ELN 441958
- 7-chloro-2-[3-(9-pyridin-4-yl-3,9-diazaspiro[5.5]undecane-3-carbonyl)phenyl]-3H-isoindol-1-one ELN441958
- CS-1805
- 1H-Isoindol-1-one, 7-chloro-2,3-dihydro-2-[3-[[9-(4-pyridinyl)-3,9-diazaspiro[5.5]undec-3-yl]carbonyl]phenyl]-
- low CNS exposure,ELN-441958,Inhibitor,anti-hyperalgesic,ELN441958,Bradykinin Receptor,inhibit,high oral bioavailability
- ELN-441958, 10 mM in DMSO
- CAS:
- 913064-47-8
- MF:
- C29H29ClN4O2
- MW:
- 501.02
- EINECS:
- 604-604-1
- Product Categories:
-
- Inhibitors
- Mol File:
- 913064-47-8.mol
ELN 441958 Chemical Properties
- Boiling point:
- 738.4±60.0 °C(Predicted)
- Density
- 1.37±0.1 g/cm3(Predicted)
- storage temp.
- 2-8°C
- solubility
- Soluble in DMSO
- form
- Powder
- pka
- 10.87±0.10(Predicted)
- color
- White to off-white
ELN 441958 Usage And Synthesis
Uses
ELN-441958 is a potent, neutral, competitive and selective bradykinin B1 receptor antagonist with a Ki of 0.26 nM against native human bradykinin B1 receptor. ELN-441958 has high oral bioavailability, and has low CNS exposure in the mouse[1].
Biological Activity
eln441958 is a novel, potent and selective bradykinin b1 receptor antagonist with ki value of 0.26 nm [1].the bradykinin b1 receptor is a g-protein coupled receptor with principal ligand of bradykinin and plays an important role in chronic pain and inflammation [1].eln441958 is a novel, potent and selective bradykinin b1 receptor antagonist. in imr-90 lung fibroblast cell membranes, eln441958 competitively inhibited the binding of the agonist [3h]dakd to the human b1 receptor with ki value of 0.26 nm. in imr-90 cells expressing the native human b1 receptor, eln441958 concentration-dependently antagonized calcium mobilization induced by dakd with kb value of 0.12 nm. eln441958 is highly selective for b1 over b2 receptors. eln441958 failed to inhibit the calcium mobilization induced by b2-receptor agonist bk. eln441958 also inhibited human μ-, δ-, κ- opioid receptors and muscarinic m1 receptor with ki values of 0.13, 0.69, 1.5 and 0.37 μm, respectively. eln441958 is also an agonist at the δ-opioid receptor (ec50 = 0.76 μm) and μ-opioid receptor. in vitro, eln441958 exhibited good permeability and metabolic stability [1].in rats and rhesus monkeys, eln441958 exhibited high oral bioavailability and moderate plasma half-lives. in rhesus monkeys, eln441958 dose-dependently reduced the thermal hyperalgesia induced by carrageenan with ed50 value of ~3 mg/kg s.c [1].
in 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.) exhibits a favorable pharmacokinetic profile in the rat and rhesus monkey[1].
| Animal Model: | Adult male and female rhesus monkeys[1] |
| Dosage: | 1, 3, or 10 mg/kg |
| Administration: | Subcutaneous injection, 30 min before carrageenan injection |
| Result: | Increased the tail-withdrawal latencies in a dose-dependent manner. |
| Animal Model: | Rhesus monkeys or Sprague-Dawley rats[1] |
| Dosage: | 2.5 or 10 mg/kg for rats, 1 mg/kg or 5 mg/kg for rhesus monkeys |
| Administration: | Intravenous injection (2.5 mg/kg and 1 mg/kg) or oral administration (10 mg/kg and 5 mg/kg) (Pharmacokinetic Analysis) |
| Result: | In rats: When dosed intravenously, showed a moderate volume of distribution (2.7 L/kg, approximately four times total body water) and a moderate clearance (0.96 L/h/kg, approximately 24% of hepatic blood flow). The terminal plasma half-life of this compound in rats was 1.7 h. When dosed orally, the concentrations increased to a maximum of 1.2 g/mL at 2 h after dosing. The oral availability was 57%. In rhesus monkeys: When dosed intravenously, showed a moderate volume of distribution (2.7 L/kg) and a moderate clearance (0.49 L/h/kg, approximately 32% of hepatic blood flow). The terminal plasma half-life was 3.9 h. When dosed orally, the concentrations increased to a maximum of 3.6 g/mL at 3.3 h after dosing. The calculated oral bioavailability was greater than 100%. |
References
[1]. hawkinson je, szoke bg, garofalo aw, et al. pharmacological, pharmacokinetic, and primate analgesic efficacy profile of the novel bradykinin b1 receptor antagonist eln441958, j pharmacol exp ther, 2007, 322(2): 619-630.
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