CI-959 free acid
CI-959 free acid is an orally active cell activation inhibitor. CI-959 free acid selectively suppresses inflammatory cell activation post-receptor signaling via inhibiting calcium influx and weak calmodulin antagonism, without targeting PLC, PKC or NADPH oxidase. CI-959 free acid blocks lung allergic mediator release, anti-IgE bronchial contraction, neutrophil function, T-cell proliferation and DC marker expression while sparing monocytes. CI-959 free acid provides gastric cytoprotection by inhibiting leukocyte adhesion and suppresses tumor motility through F-actin reduction. CI-959 free acid can be used for research on allergies, inflammation, autoimmune diseases, gastric injury, and tumor metastasis .
For research use only. We do not sell to patients.
- CAS No.: 104795-66-6
- Formula: C14H15N5O3S
- Molecular Weight:333.37
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Storage:
Please store the product under the recommended conditions in the Certificate of Analysis.
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Biological Activity
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Chemical Information
- Purity & Documentation
- References
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Biological Activity
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Calcium Channel |
F-actin |
CI-959 (0.1-100 μM) free acid inhibits spontaneous neutrophil migration and fMLP-induced chemotaxis in human peripheral blood neutrophils, with IC50 values of 3.6 and 3.1 μM, respectively[3].
CI-959 (100 μM) free acid shows no significant inhibition of fMLP receptor binding in human peripheral blood neutrophils, but only mildly inhibits phagocytosis of opsonized yeast[3].
CI-959 (0.1-100 μM) free acid selectively inhibits respiratory burst induced by stimuli that promote calcium mobilization or calcium influx in human peripheral blood neutrophils, but does not act on NADPH oxidase itself and does not have oxygen free radical scavenging activity[3].
CI-959 (0.1-100 μM) free acid selectively suppresses primary granule degranulation, with negligible activity against secondary granule secretion and PKC-dependent degranulation; it has no direct enzyme inhibition or cytotoxicity in human peripheral blood neutrophils[3].
CI-959 free acid acts upstream of arachidonic acid metabolism via calcium signaling, without direct inhibition of 5-LO or COX enzymes in human peripheral blood neutrophils[3].
CI-959 (100 μM) free acid targets downstream of PLC and IP3 receptor, blunts neutrophil calcium signaling by inhibiting extracellular Ca2+PKC in human peripheral blood neutrophils[3].
CI-959 (5-10 μM) free acid directly blocks inflammatory mediator-induced leukocyte-endothelial adhesion without disturbing microcirculatory hemodynamics[4].
CI-959 (0.0075-75 μM; 10 min) free acid potently inhibits immunologically induced mediator release from human and guinea pig lung in vitro, with marked suppression of histamine and leukotriene release[5].
CI-959 (1-10 μM; 10 min) free acid almost completely inhibits anti-IgE-induced human bronchial smooth muscle contraction[5].
CI-959 (0.3-100 μM; 24 h) free acid concentration-dependently inhibits Con A (Concanavalin A (Biotinylated)) (HY-NP0174)-stimulated IL-2 release in rat spleen cells and human lymphocytess[6].
CI-959 (0.03-300 μM) free acid potently suppresses ConA-triggered proliferation (IC50=4.7 μM for rat splenocytes, 5.4 μM for human lymphocytes) and MLR responses (IC50=3.5 μM), and this ConA inhibitory effect cannot be rescued by exogenous IL-2s[6].
CI-959 (0.01-100 μM) free acid rapidly and in a concentration-dependent manner inhibits the spontaneous polarity of Walker carcinosarcoma cells, and this effect is reversible[7].
CI-959 (10 μM; 30 min) free acid almost completely inhibits the spontaneous motility of Walker carcinosarcoma cells[7].
CI-959 (0.001-100 μM) free acid concentration-dependently reduces F-actin content in Walker carcinosarcoma cells, closely correlating with inhibition of cell polarity[7].
CI-959 (0.01-30 μM; 30 min) free acid inhibition of Walker cell polarity is independent of extracellular calcium[7].
CI-959 (30 μM) free acid only induces minor shifts of intracellular calcium, and its anti-motile function persists under low-calcium conditions, ruling calcium signaling as its primary mechanism[7].
CI-959 (1-100 μM; 24-72 h) free acid has no direct hypertrophic effect on cardiomyocytes; cardiac hypertrophy is not a direct compound effect[8].
CI-959 (0.67 nM-6.7 μM; 30 min) free acid has minimal direct β-adrenoceptor binding activity, ruling out direct catecholaminergic effects[8].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
| Species | Dose | Route | Cmax | AUC |
|---|---|---|---|---|
| Rat[8] | 10 mg/kg | i.v. | 69 μg/mL | 27.6 μg·h/mL |
| Rat[8] | 100 mg/kg | p.o. | 24.1 μg/mL | 311 μg·h/mL |
| Rat[8] | 150 mg/kg | p.o. | 36.6 μg·h/mL | 606 |
| Rat[8] | 20 mg/kg | i.v. | 142 μg/mL | 152 μg·h/mL |
| Rat[8] | 25 mg/kg | p.o. | 6.02 μg/mL | 35.1 μg·h/mL |
| Rat[8] | 3 mg/kg | i.v. | 23.9 μg/mL | 2.43 μg·h/mL |
| Rat[8] | 30 mg/kg | i.v. | 174 μg/mL | 557 μg·h/mL |
| Rat[8] | 50 mg/kg | p.o. | 13.5 μg/mL | 109 μg·h/mL |
CI-959 (10-90 mg/mL; intranasal instillation; once daily; for 14 days) free acid has local toxicity to the respiratory epithelium of the canine nasal cavity[1].
CI-959 free acid (25-75 mg/kg; p.o.; once daily; for 14 days) exhibits no significant immunotoxicity in rats at doses that do not alter body weight or organ weights[2].
CI-959 (25-75 mg/kg; p.o.; once daily; for 14 days) free acid does not impair the host resistance of mice to bacteria and tumors[2].
CI-959 (0.0001-100 mg/kg; p.o.; single dose) free acid exhibits potent cytoprotective activity against NSAID (Aspirin (HY-14654), Indomethacin (HY-14397)) and ethanol-induced gastric mucosal damage in Sprague-Dawley rat, with ED50 values of 0.05 mg/kg (aspirin), 1.0 mg/kg (indomethacin), and 0.07 mg/kg (ethanol), respectively[4].
CI-959 (5 mg/kg; p.o.; single dose) free acid prophylactic administration reduces the severity of gastric damage but does not accelerate the healing process after injury in Sprague-Dawley rat[4].
CI-959 (5 mg/kg; p.o.; once daily) free acid has no significant effect on the healing rate of gastric injuries induced by ethanol or indomethacin in Sprague-Dawley rat[4].
CI-959 (50-200 mg/kg; p.o.; single dose) free acid does not inhibit gastric acid secretion in a rat basal gastric acid secretion model[4].
CI-959 (0.1-10 mg/kg; p.o.; single dose) free acid dose not inhibit gastric acid secretion in a Beagle dog model of stimulated gastric acid secretion[4].
CI-959 (2-50 mg/kg; p.o.; single dose) free acid’s protective effect on gastric cells does not involve the inhibition of the arachidonic acid metabolic pathway in Sprague-Dawley rat[4].
CI-959 (0.1-100 mg/kg; p.o.; single dose) free acid does not exert cytoprotective effects via regulating intracellular sulfhydryl levels in Sprague-Dawley rat[4].
CI-959 (1-10 mg/kg; p.o.; single dose) free acid effectively inhibits indomethacin-induced leukocyte adhesion in Sprague-Dawley rat[4].
CI-959 (25 mg/kg; i.v.; single dose) free acid exhibits gastric cytoprotection after intravenous administration in Sprague-Dawley rat, indicating that its protective effect is independent of local gastrointestinal effects[4].
CI-959 (3-30 mg/kg; i.v.; once daily; for 14 days) free acid induces reversible cardiac hypertrophy in male Wistar rats, with no myocardial injury or CPK/LDH isozyme changes[8].
CI-959 (30-100 mg/kg; i.v.; once daily; for 10.5 days) free acid fails to induce cardiac hypertrophy without high plasma drug peaks in Male Wistar rats, confirming Cmax as the critical toxic determinant[8].
CI-959 (25 mg/kg; i.v.; once daily; for 10 days) free acid-associated cardiac hypertrophy is mediated by endogenous catecholaminergic stimulation of cardiac β1-adrenoceptors in Male Wistar rats[8].
CI-959 (100 mg/kg; p.o.; once daily; for 7 days) free acid only triggers mild transient hypotension and slight brief catecholamine elevation in Male Wistar rats, while dopamine levels stay constant[8].
CI-959 (25 mg/kg; i.v.; once daily; for 7 days) free acid induces persistent hypotension and marked rises in plasma epinephrine and norepinephrine without compensatory tachycardia in Male Wistar rats[8].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
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Animal Model:Wistar rats (85-127 days old, weighing 253-367 g)[1]
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Dosage:0.5 mg/mL, 2 mg/mL, 10 mg/mL, 20 mg/mL, 30 mg/mL, 60 mg/mL, 90 mg/mL
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Administration:Intranasal instillation, once daily, for 14 days
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Result:Did not cause nasal lesions at 0.5 mg/mL.
Only a few small degenerative foci of the olfactory epithelium in a small number of female animals at 2 mg/mL.
Dose-dependent nasal mucosal degeneration was detected at all four nasal tissue levels in rats, characterized by epithelial disorganization, intracellular edema, mucosal thinning, cellular sloughing and necrosis at concentrations ≥10 mg/mL.
Adhesions and fibrous osteophytes appeared at concentrations ≥20 mg/ml.
Bilateral lesions and serous luminal exudate appeared at 60-90 mg/mL.
Increased salivation was observed in male mice at concentrations ≥20 mg/mL.
Increased salivation was observed in female mice at concentrations ≥60 mg/mL.
Decreased body weight or reduced weight gain was observed in female mice in the 60-90 mg/mL group.
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Animal Model:Beagle dogs (Marshall Farms),(1-3 years old, weighing 8-14 kg)[1]
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Dosage:10 mg/mL, 20 mg/mL, 30 mg/mL, 60 mg/mL, 90 mg/mL
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Administration:Intranasal instillation, once daily, for 14 days
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Result:No nasal mucosal damage was observed at 10 mg/mL.
Respiratory epithelial degeneration occurred at concentrations ≥20 mg/ml, characterized by loss of cilia and goblet cells, mucosal thinning, and squamous or transitional metaplasia; lesion severity and extent increased with concentration.
Almost all dogs treated with the medication experienced salivation, but this was not related to the dosage.
Had no effect on body weight, food intake, or body temperature.
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Animal Model:Male Fischer 344 rats (6-7 weeks)[2]
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Dosage:25 mg/kg, 50 mg/kg, 75 mg/kg
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Administration:p.o., once daily, for 14 days
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Result:Had no significant effect on the percentage of T and B cells in the spleen or the total number of spleen cells.
Significantly reduced NK cell activity, but in no dose-dependent manner.
Had no significant effect on Con A and PWM-induced lymphocyte proliferation.
Significant reductions in AFC/106 cells and AFC/spleen at 75 mg/kg were observed on days 4 and 5.
Reduced spleen weight, but had no significant effect on the clearance half-life of 51Cr-sRBCs, liver and spleen uptake.
Significantly reduced NK cell activity (approximately 15-18% inhibition) at 50 and 75 mg/kg, but this was not dose-dependent.
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Animal Model:Female B6C3F1 mice (6-8 weeks)[2]
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Dosage:25 mg/kg, 50 mg/kg, 75 mg/kg
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Administration:p.o., once daily, for 14 days
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Result:None of the bacterial challenge doses altered the host resistance of mice to Streptococcus pneumoniae.
None of the bacterial challenge doses altered the host resistance of mice to Listeria monocytogenes.
The number of lung nodules and CPM/lung ratio were comparable to those in the control group at each tumor cell attack dose.
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Animal Model:Female Sprague-Dawley rats weighting 180-300 g[4]
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Dosage:0.0001-100 mg/kg
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Administration:p.o., single dose
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Result:Provided dose-dependent gastric mucosal protection against aspirin (ED50 = 0.05 mg/kg), indomethacin (ED50 = 1.0 mg/kg), and ethanol (ED50 = 0.07 mg/kg).
Prevented ethanol-induced mucosal and submucosal edema and hemorrhage at 10 mg/kg.
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Animal Model:Female Sprague-Dawley rats weighting 180-300 g[4]
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Dosage:5 mg/kg
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Administration:p.o., single dose
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Result:Showed lower damage levels than the solvent group at all time points, with an average cytoprotective effect of approximately 86%, but the healing rate was parallel to that of the solvent group.
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Animal Model:Female Sprague-Dawley rats weighting 180-300 g[4]
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Dosage:5 mg/kg
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Administration:p.o., once daily
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Result:Had no significant effect on the healing rate of gastric injuries induced by ethanol or indomethacin.
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Animal Model:Shay pylorus-ligated rat weighting 140-240 g[4]
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Dosage:50 mg/kg, 200 mg/kg
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Administration:p.o., single dose
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Result:Had no significant effect on basal gastric acid secretion.
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Animal Model:Gastric fistula female beagle dogs weighting 7-11 kg[4]
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Dosage:0.1 mg/kg, 1 mg/kg, 10 mg/kg
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Administration:p.o., single dose
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Result:Had no effect on Dimaprit (Dimaprit dihydrochloride) (HY-B1478)-stimulated gastric acid secretion.
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Animal Model:Female Sprague-Dawley rats weighting 180-300 g[4]
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Dosage:2 mg/kg, 10 mg/kg, 50 mg/kg
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Administration:p.o., single dose
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Result:Had no significant inhibitory effect on the production of PGE2 and LTC4 in the gastric mucosa stimulated by ethanol.
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Animal Model:Female Sprague-Dawley rats weighting 180-300 g[4]
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Dosage:0.1 mg/kg, 1 mg/kg, 10 mg/kg, 100 mg/kg combined with NEM (50 mg/kg)
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Administration:p.o. combined with NEM (s.c.), single dose
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Result:Showed no significant change in gastric cytoprotection after NEM ( N-Ethylmaleimide) (HY-D0843) co-administration.
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Animal Model:Female Sprague-Dawley rats weighting 180-300 g[4]
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Dosage:1 mg/kg, 5 mg/kg, 10 mg/kg
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Administration:p.o., single dose
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Result:Completely inhibited indomethacin-induced leukocyte adhesion at 5 and 10 mg/kg.
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Animal Model:Female Sprague-Dawley rats weighting 180-300 g[4]
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Dosage:25 mg/kg
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Administration:i.v., single dose
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Result:Exhibited gastric cytoprotection after intravenous administration.
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Animal Model:Male Wistar rats (weighting 150-250 g)[8]
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Dosage:3 mg/kg, 10 mg/kg, 30 mg/kg
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Administration:i.v., once daily, for 14 days
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Result:No cardiac morphological or biochemical changes at 3 mg/kg for 14 days.
Ventricular wall thickening and massive myocardial glycogen accumulation appeared at day 7 with 10 and 30 mg/kg.
Right ventricular hypertrophy occurred at day 14 for 30 mg/kg.
Glycogen accumulation and myocyte enlargement; no degeneration or necrosis, all these changes completely reversible after 14-day withdrawal.
Increased Heart wet weight, dry weight, and total protein.
Induced cardiac hypertrophy was not associated with CPK or LDH isozyme changes.
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Animal Model:Male Wistar rats (weighting 150-250 g)[8]
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Dosage:30 mg/kg
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Administration:i.v., once daily, for 10.5 days
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Result:Daily IV bolus increased heart weight by 35%.
Ontinuous infusion at 30/100 mg/kg/day resulted in steady-state plasma levels of only 3.1 and 10 μg/mL.
Continuous infusion had no effect on heart weight.
Was undetectable in plasma 24 hours after the last administration in the intravenous bolus group.
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Animal Model:Male Wistar rats (weighting 150-250 g)[8]
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Dosage:25 mg/kg
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Administration:i.v., once daily, for 10 days
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Result:Triggered cardiac hypertrophy and glycogen accumulation were completely abolished by central sympatholytics (Clonidine (HY-12721)), nonselective β-blockers (D,L-propranolol and L-propranolol) and β₁-selective antagonists (Atenolol (HY-17498) and Practolol (HY-119802)).
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Animal Model:Male Sprague-Dawley rats (weighting 328-477 g)[8]
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Dosage:100 mg/kg
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Administration:p.o., once daily, for 7 days
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Result:Produced only slight BP reduction of 11 mmHg.
Produced only transient catecholamine increase, returning by 4 h.
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Animal Model:Male Sprague-Dawley rats (weighting 328-477 g)[8]
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Dosage:25 mg/kg
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Administration:i.v., once daily, for 7 days
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Result:Produced sustained BP reduction of 20-26 mmHg, maximal at 1-2 h, recovery at 5-6 h.
Produced significant and prolonged increase in plasma Epi and NE, peaking at 1 h, sustained for at least 4 h.
Chemical Information
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CAS No. 104795-66-6
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Molecular Weight 333.37
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Formula C14H15N5O3S
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SMILES
O=C(C1=C(OC(C)C)C2=CC(OC)=CC=C2S1)NC3=NNN=N3
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Shipping
Room temperature in continental US; may vary elsewhere.
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Storage
Please store the product under the recommended conditions in the Certificate of Analysis.
Purity & Documentation
References
[1]. Walsh KM, et al. Nasal toxicity of CI-959 free acid, a novel anti-inflammatory drug, in Wistar rats and Beagle dogs. Toxicol Pathol. 1998 Nov-Dec;26(6):717-23. [Content Brief]
[2]. Bleavins MR, et al. Immunotoxicologic studies with CI-959 free acid, a novel benzothiophene cell activation inhibitor. Toxicology. 1995 Apr 12;98(1-3):111-23. [Content Brief]
[3]. Wright CD, et al. Selective regulation of human neutrophil functions by the cell activation inhibitor CI-959 free acid. J Leukoc Biol. 1994 Apr;55(4):443-51. [Content Brief]
[4]. Low J, et al. Cytoprotective effects of CI-959 free acid in the rat gastric mucosa: modulation of leukocyte adhesion. Gastroenterology. 1995 Oct;109(4):1224-33. [Content Brief]
[5]. Adolphson RL, et al. CI-959 free acid, a new, potential antiallergic drug, inhibits mediator release from lung and contractions of human airways in vitro. Int Arch Allergy Appl Immunol. 1990;93(2-3):267-71. [Content Brief]
[6]. Dong MK, et al. Inhibition of interleukin-2 production and lymphocyte responsiveness by the cell activation inhibitor, CI-959 free acid. Agents Actions. 1991 Sep;34(1-2):53-5. [Content Brief]
[7]. von Tscharner Biino N, et al. Suppression of polarity, locomotion and F-actin levels of Walker carcinosarcoma cells by the inhibitor CI-959 free acid. Life Sci. 1997;61(2):137-45. [Content Brief]
[8]. Low JE, et al. Cardiac hypertrophy in rats after intravenous administration of CI-959 free acid, a novel antiinflammatory compound: morphologic features and pharmacokinetic and pharmacodynamic mechanisms. J Cardiovasc Pharmacol. 1995 Jun;25(6):930-9. [Content Brief]
Calculators
Concentration (start) × Volume (start) = Concentration (final) × Volume (final)
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