CI-1018
CI-1018 is an orally active selective PDE-4 inhibitor, with IC50 values of 1.1 μM, 35.8 μM, and 73.4 μM against hPDE-4, canine PDE-4, and guinea pig PDE-4, respectively. CI-1018 induces iNOS expression and Apoptosis. CI-1018 induces vascular injury, medial necrosis, hemorrhage, edema, thymic atrophy, ketonuria, and weight loss. CI-1018 can be used in research related to asthma, vasculitis, and mesenteric vasculitis/arteriopathy.
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- No. CAS: 245329-99-1
- Fòrmula: C24H20N4O2
- Peso molecular:396.45
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Almacenamiento:
Please store the product under the recommended conditions in the Certificate of Analysis.
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Actividad biológica
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Chemical Information
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Actividad biológica
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PDE4 1.1 μM (IC50) |
iNOS |
CI-1018 inhibits PDE4 derived from U937 cells with an IC50 of 1.1 μM, while it shows weak inhibitory effects on PDE3 derived from canine aorta and PDE1/PDE5 derived from guinea pig trachea[3].
CI-1018 inhibits TNF-α release from peripheral blood mononuclear cells, with an IC50 of 0.990 μM[3].
CI-1018 inhibits the release of TNF-α in human whole blood (hWB) with an IC50 of 61 μM[3].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
CI-1018 (administered orally, once 24 h and once 3 h prior to antigen challenge) inhibits antigen-induced airway eosinophil recruitment in sensitized Brown-Norway rats, with an oral ED50 of 5.06 mg/kg[3].
CI-1018 (10 mg/kg; p.o.) inhibits LPS-induced TNFα release by 25% in Wistar rats at an oral dose of 10 mg/kg[3].
CI-1018 (750 mg/kg; p.o.; once daily; for 4 consecutive days) induces significant mesenteric vasculitis in female Wistar rats, accompanied by nitrative stress and medial smooth muscle cell apoptosis, whereas co-administration with Dexamethasone (HY-14648) abolishes the inflammatory response, markers of nitrative stress, and apoptotic phenomena[4].
CI-1018 (750 mg/kg; p.o.; once daily; for 3 consecutive days) induces mesenteric vasculitis in female Wistar rats and mediates caspase-3 activation in their medial smooth muscle cells; neutrophil depletion reduces the severity of vasculitis but fails to eliminate caspase-3 immunoreactivity[4].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
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Animal Model:Crl:WI (female, approximately 207-209 g pretest weight)[1]
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Dosage:750 mg/kg
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Administration:p.o.; daily; 4 days
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Result:Exhibited a mean body weight change of -3 g from pretest.
Developed marked mesenteric vasculitis in all 6 rats, with 2 rats also developing mild hepatic portal artery vasculitis, and minimal to moderate thymic atrophy in all rats.
Showed clear urinary principal component analysis pattern separation within 48-72 hours compared to vehicle controls.
Had β-hydroxybutyrate detected in 3 of 6 rats, at absolute concentrations up to 300 mM.
Showed decreases in Krebs cycle intermediates (citrate, succinate, 2-oxoglutarate), hippurate, taurine, and trimethylamine-N-oxide.
When co-administered with dexamethasone, 5 of 6 rats developed minimal arteriopathy, with urinary principal component analysis pattern shifts identical to CI-1018 alone in 5 of 6 rats, and no pattern shift in the single rat without vascular lesions.
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Animal Model:Wistar rats (female, adult, acclimated for 7 days prior to study)[4]
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Dosage:750 mg/kg
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Administration:p.o.; daily; 4 consecutive days
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Result:Induced mild to marked multifocal mesenteric vasculitis characterized by medial necrosis, hemorrhage, mixed inflammatory cell infiltrates in the media and adventitia, perivascular edema/fibrin, granulation tissue, and plump reactive endothelial cells in all 6 rats treated alone.
Showed intense iNOS immunoreactivity in endothelial cells and inflammatory cell infiltrates, significant nitrotyrosine immunoreactivity in inflammatory cell infiltrates, TUNEL-positive staining in medial smooth muscle cells, and caspase-3 immunoreactivity in medial smooth muscle cells and inflammatory cell infiltrates in rats treated alone.
Exhibited minimal mesenteric arteriopathy (multifocal minimal medial necrosis, degeneration, vacuolation of smooth muscle cells, and rare medial red blood cells) with no accompanying inflammation when co-administered with dexamethasone.
Eliminated TUNEL, caspase-3, iNOS, and nitrotyrosine immunoreactivity when co-administered with dexamethasone.
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Animal Model:Wistar rats (female, adult, acclimated for 7 days prior to study)[4]
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Dosage:750 mg/kg
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Administration:p.o.; daily; 3 consecutive days
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Result:Induced mild to marked mesenteric vasculitis with histopathologic features identical to CI-1018-only treated rats in 4 of 6 rats when co-administered with normal rabbit serum.
Detected caspase-3 immunoreactivity in medial smooth muscle cells in rats treated with CI-1018 plus normal rabbit serum.
Reduced circulating neutrophil counts throughout the study when co-administered with anti-rat PMN antiserum.
Decreased the incidence and severity of CI-1018-induced vasculitis when co-administered with anti-rat PMN antiserum.
Resulted in minimal mesenteric arteriopathy (smooth muscle cell degeneration, vacuolation, minimal hemorrhage, and no to minimal mononuclear cell infiltration) when co-administered with anti-rat PMN antiserum.
Left caspase-3 immunoreactivity in medial smooth muscle cells detectable when co-administered with anti-rat PMN antiserum.
Chemical Information
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No. CAS 245329-99-1
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Peso molecular 396.45
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Fòrmula C24H20N4O2
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SMILES
O=C(NC1N=C(C=2C=CC=CC2)C=3C=C(C=C4C3N(C1=O)CC4)C)C=5C=CN=CC5
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Envío
Room temperature in continental US; may vary elsewhere.
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Almacenamiento
Please store the product under the recommended conditions in the Certificate of Analysis.
Pureza y Documentación
Referencias
[1]. Slim RM, et al. Effect of dexamethasone on the metabonomics profile associated with phosphodiesterase inhibitor-induced vascular lesions in rats. Toxicology and applied pharmacology. 2002 Sep 01;183(2):108-9. [Content Brief]
[2]. Robertson DG, et al. Metabonomic assessment of vasculitis in rats. Cardiovascular toxicology. 2001;1(1):7-19. [Content Brief]
[3]. Burnouf C, et al. Synthesis, structure-activity relationships, and pharmacological profile of 9-amino-4-oxo-1-phenyl-3,4,6,7-tetrahydro[1,4]diazepino[6, 7,1-hi]indoles: discovery of potent, selective phosphodiesterase type 4 inhibitors. Journal of medicinal chemistry. 2000 Dec 14;43(25):4850-67. [Content Brief]
[4]. Slim RM, et al. Apoptosis and nitrative stress associated with phosphodiesterase inhibitor-induced mesenteric vasculitis in rats. Toxicologic pathology. 2003;31(6):638-45. [Content Brief]
Calculators
Concentration (start) × Volume (start) = Concentration (final) × Volume (final)
CI-1018 Related Classifications
HY-19299 Related Classifications
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