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SSR-240612 HCl

Alias: SSR240612; SSR-240612 hydrochloride; SSR 240612; SSR240612 HCl
Cat No.:V3106 Purity: ≥98%
COA Product Data Instructions for use SDS
SSR-240612 HCl, the hydrochloride salt of SSR240612, is a novel, potent, and orally bioactive specific non-peptide bradykinin B(1) receptor antagonist.
SSR-240612 HCl Chemical Structure CAS No.: 464930-42-5
Product category: Bradykinin Receptor
This product is for research use only, not for human use. We do not sell to patients.
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Purity & Quality Control Documentation

Purity: ≥98%

COA
MSDS
Instructions
Product Description

SSR-240612 HCl, the hydrochloride salt of SSR240612, is a novel, potent, and orally bioactive specific non-peptide bradykinin B(1) receptor antagonist. SSR-240612 has the potential for the treatment of inflammation and chronic pain. In human fibroblast MRC5 and recombinant human B(1) receptor expressed in human embryonic kidney cells, SSR240612 inhibits the binding of [(3)H]Lys(0)-des-Arg(9)-BK to the B(1) receptor. The inhibition constants (K(i)) of these two receptors are 0.48 and 0.73 nM, respectively. With an IC(50) of 1.9 nM, SSR240612 prevented human fibroblast MRC5 from forming inositol monophosphate in response to Lys(0)-desAr(9)-BK (10 nM). Also, it inhibited the des-Arg(9)-BK-induced contractions in the rat ileum's mesenteric plexus and isolated rabbit aorta, with pA(2) values of 8.9 and 9.4, respectively.

Biological Activity I Assay Protocols (From Reference)
Targets
bradykinin B1 receptor, Human MRC5 ( Ki = 0.48 nM );
bradykinin B1 receptor, Human HEK-B1 ( IC50 = 0.73 nM );
bradykinin B2 receptor, guinea pig ileum membranes ( IC50 = 481 nM );
bradykinin B2 receptor, Human CHO-B2 ( IC50 = 358 nM )
ln Vitro

In vitro activity: SSR240612 is a strong antagonist of the bradykinin B1 receptor, with Kis values of 0.48 nM and 0.73 nM for the B2 kinin receptors of human fibroblast MRC5 and HEK cells that express human B1 receptors, respectively, and 481 nM and 358 nM for the B1 receptors of guinea pig ileum membranes and CHO cells that express human B1 receptor. The human fibroblast MRC5 is activated by BK (3 nM) to produce inositol phosphate-1, but SSR240612 inhibits this formation with an IC50 of 1.9 nM and has no discernible effect on this process[1].
ln Vivo
SSR240612 (10 mg/kg p.o. or 0.3, 1 mg/kg i.p.) clearly prevents the mice's paw edema caused by des-Arg9-BK. In the formalin model of inflammation in mice, SSR240612 (10 and 30 mg/kg) reduces, in a dose-dependent manner, the duration of the late phase of paw licking. The administration of SSR240612 (0.3, 3, and 30 mg/kg, p.o.) prior to capsaicin therapy potently and independently of concentration decreases ear edema. Following splanchnic artery occlusion/reperfusion, SSR240612 (0.3 mg/kg, i.v.) also inhibits tissue deterioration and neutrophil accumulation in the rat colon. Furthermore, SSR240612 (1 and 3 mg/kg p.o.) dramatically lengthens the withdrawal latencies in rats experiencing UV-induced thermal hyperalgesia[1]. In rats fed glucose, SSR240612 attenuates tactile and cold allodynia at 3 hours, but it had no effect on control rats, whose ID50s were 5.5 and 7.1 mg/kg, respectively. In rats given glucose at a dose of 10 mg/kg, SSR240612 has no effect on insulin resistance (HOMA index), plasma glucose and insulin, or the generation of aortic superoxide anion[2].
Enzyme Assay
[3H]Lys0-des-Arg9-BK The following ingredients make up the binding buffer used for binding to cell membranes: 137 mM NaCl, 5.4 mM KCl, 1.05 mM MgCl2, 1.8 mM CaCl2, 1.2 mM NaH2PO4, 15.5 mM NaHCO3, 10 mM HEPES, 1 g/L bovine serum albumin (BSA), 140 mg/L bacitracin, and 1 μM captopril, pH 7.4. The membranes are incubated in 500 μL of binding buffer containing 1 nM [3H]Lys0-des-Arg9-BK for 30 minutes at 25°C. for saturation isotherms and 0.1 to 10 nM for competition curves. Filters are washed three times with 5 mL of binding buffer, and radioactivity is determined by liquid scintillation spectrometry. One way to measure nonspecific binding is to add 1 μM of unlabeled Lys0-des-Arg9BK[1].
Cell Assay
SSR240612 is a strong antagonist of the bradykinin B1 receptor, with Kis values of 0.48 nM and 0.73 nM for the B2 kinin receptors of human fibroblast MRC5 and HEK cells that express human B1 receptors, respectively, and 481 nM and 358 nM for the B1 receptors of guinea pig ileum membranes and CHO cells that express human B1 receptor. SSR240612 inhibits the formation of inositol phosphate-1 with an IC50 of 1.9 nM, but has no discernible effect on the formation of inositol phosphate-1 in human fibroblast MRC5 that is triggered by BK (3 nM) activation of the B2 receptor.
Animal Protocol
Mice: Groups of eight male albino mice are given an intraplantar injection (20 μL) containing 5 μg of IL-1β in phosphate-buffered saline/0.1% BSA into their right hind paw while they are under isoflurane anesthesia. Subject to anesthesia, mice are given a 20-μL intraplantar injection of des-Arg9-BK (10 μg/paw) in water forty minutes later (T = 0). Acute administration of SSR240612 or vehicle (5% (v/v) ethanol and 5% (v/v) Tween 80 in water) is done by intraperitoneal route 40 minutes prior to des-Arg9-BK injection, and orally at doses of 1, 3, and 10 mg/kg one hour before the injection. Paw volume is measured using a plethysmometer at T = -2 hours (first measurement) and at multiple intervals (T = 20, 40, 60, and 120 min) following edema induction. The difference between the initial paw volume and the paw volume at each time after edema induction is the paw edema volume, measured in milliliters. The mean ± S.E.M. of the individual paw edema volumes is presented for each group. After confirming the normality and homogeneity of variances with multiple ANOVA tests, Duncan's test is used to compare the treated groups to the des-Arg9-BK control group[1]. Rats: SSR240612 (suspended with 0.1% Tween 80 in saline) is given orally, two hours prior to the thermal hyperalgesia measurement, at a dose of 20 milliliters per kilogram. Prior to measuring the rats' withdrawal latencies in the time course study, the compound is given orally at a dose of 3 mg/kg at intervals of 0.08, 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours. The results are given as mean withdrawal latencies (s) ± S.E.M. in seconds, and statistical analyses are carried out with a two-way ANOVA and Dunnett's test[1].
References

[1]. SSR240612 [(2R)-2-[((3R)-3-(1,3-benzodioxol-5-yl)-3-[[(6-methoxy-2-naphthyl)sulfonyl]amino]propanoyl)amino]-3-(4-[[2R,6S)-2,6-dimethylpiperidinyl]methyl]phenyl)-N-isopropyl-N-methylpropanamide hydrochloride], a new nonpeptide antagonist of the bradykinin B1 receptor: biochemical and pharmacological characterization. J Pharmacol Exp Ther . 2004 May;309(2):661-9

[2]. The kinin B1 receptor antagonist SSR240612 reverses tactile and cold allodynia in an experimental rat model of insulin resistance. Br J Pharmacol . 2007 Sep;152(2):280-7.
These protocols are for reference only. InvivoChem does not independently validate these methods.
Physicochemical Properties
Molecular Formula
C42H53CLN4O7S
Molecular Weight
793.42
Exact Mass
792.33
Elemental Analysis
C, 63.58; H, 6.73; Cl, 4.47; N, 7.06; O, 14.12; S, 4.04
CAS #
464930-42-5
Related CAS #
465539-70-2
Appearance
Solid powder
SMILES
C[C@@H]1CCC[C@@H](N1CC2=CC=C(C=C2)C[C@H](C(=O)N(C)C(C)C)NC(=O)C[C@H](C3=CC4=C(C=C3)OCO4)NS(=O)(=O)C5=CC6=C(C=C5)C=C(C=C6)OC)C.Cl
InChi Key
GLHHFOSVBQQNAW-GDYXXZBVSA-N
InChi Code
InChI=1S/C42H52N4O7S.ClH/c1-27(2)45(5)42(48)38(20-30-10-12-31(13-11-30)25-46-28(3)8-7-9-29(46)4)43-41(47)24-37(34-16-19-39-40(23-34)53-26-52-39)44-54(49,50)36-18-15-32-21-35(51-6)17-14-33(32)22-36;/h10-19,21-23,27-29,37-38,44H,7-9,20,24-26H2,1-6H3,(H,43,47);1H/t28-,29+,37-,38-;/m1./s1
Chemical Name
(2R)-2-[[(3R)-3-(1,3-benzodioxol-5-yl)-3-[(6-methoxynaphthalen-2-yl)sulfonylamino]propanoyl]amino]-3-[4-[[(2R,6S)-2,6-dimethylpiperidin-1-yl]methyl]phenyl]-N-methyl-N-propan-2-ylpropanamide;hydrochloride
Synonyms
SSR240612; SSR-240612 hydrochloride; SSR 240612; SSR240612 HCl
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)
Solubility Data
Solubility (In Vitro)
DMSO: ≥ 100 mg/mL (~126.0 mM)
Water: N/A
Ethanol: N/A
Solubility (In Vivo)
Solubility in Formulation 1: ≥ 2.5 mg/mL (3.15 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 (3.15 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.
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Solubility in Formulation 3: ≥ 2.5 mg/mL (3.15 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 1.2604 mL 6.3018 mL 12.6037 mL
5 mM 0.2521 mL 1.2604 mL 2.5207 mL
10 mM 0.1260 mL 0.6302 mL 1.2604 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.

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Working concentration： mg/mL；

Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.

Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.

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Biological Data

  • SSR-240612 HCl

    Scatchard analysis of specific [3H]Lys-[des-Arg9]-bradykinin binding to B1receptors of human fibroblast MRC5 membranes in the absence (control) and presence of SSR240612.

  • SSR-240612 HCl

    Concentration-response curves for des-Arg9-BK-induced contraction of rat ileum in the absence and presence of increasing concentrations of SSR240612 from 0.3 to 30 nM.

  • SSR-240612 HCl

    Concentration-response curves for des-Arg9BK-induced contraction of rabbit aorta in the absence and presence of increasing concentrations of SSR240612 from 3 to 30 nM. Values are means ± S.E.M. (n= 4–6).

  • SSR-240612 HCl

    Effect of SSR240612 on time-dependent des-Arg9-BK-induced paw edema in mice sensitized by IL-1β.2004 May;309(2):661-9.

  • SSR-240612 HCl

    SSR240612 effects on capsaicin-induced ear inflammation in mice.2004 May;309(2):661-9.

  • SSR-240612 HCl

    Withdrawal latencies (mean ± S.E.M.) for both ultraviolet-exposed and non-exposed hind paws of rats following oral administration of SSR240612.2004 May;309(2):661-9.

  • SSR-240612 HCl

    Time course of withdrawal latencies (mean ± S.E.M.) for both ultraviolet-exposed and non-exposed hind paws of rats following oral administration of 3 mg/kg of SSR240612.2004 May;309(2):661-9.

  • SSR-240612 HCl

    Effects of SSR240612 on the late-phase paw licking response (30–40 min) induced by intraplantar injection of a 2.5% solution of formalin in mice.2004 May;309(2):661-9.

  • SSR-240612 HCl

    Antinociceptive effect of SSR240612 in a rat model of peripheral neuropathy.2004 May;309(2):661-9.

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