| Identification | Back Directory | [Name]
Paquinimod | [CAS]
248282-01-1 | [Synonyms]
ABR25757
ABR-25757
ABR 25757
ABR?215757
Paquinimod
ABR?215757; ABR 215757; ABR215757; PAQUINIMOD.
ABR 25757;ABR-25757;ABR25757;PAQUINIMOD;248282-01-1
N,5-diethyl-4-hydroxy-1-methyl-2-oxo-N-phenylquinoline-3-carboxamide
N,5-diethyl-4-hydroxy-1-methyl-2-oxo-N-phenyl-1,2-dihydroquinoline-3-carboxamide
3-Quinolinecarboxamide, N,5-diethyl-1,2-dihydro-4-hydroxy-1-methyl-2-oxo-N-phenyl- | [Molecular Formula]
C21H22N2O3 | [MDL Number]
MFCD18633277 | [MOL File]
248282-01-1.mol | [Molecular Weight]
350.41 |
| Chemical Properties | Back Directory | [Boiling point ]
487.3±45.0 °C(Predicted) | [density ]
1.267±0.06 g/cm3(Predicted) | [storage temp. ]
Sealed in dry,2-8°C | [solubility ]
DMSO:15.0(Max Conc. mg/mL);42.8(Max Conc. mM) | [form ]
A solid | [pka]
4.50±1.00(Predicted) | [color ]
White to off-white |
| Hazard Information | Back Directory | [Uses]
Paquinimod is a S100A9 inhibitor preventing S100A9 binding to TLR-4. Paquinimod reduces pathology in experimental collagenase-induced osteoarthritis. Paquinimod treatment of collagenase-induced OA (CIOA) resulted in significantly reduced synovial thickening (57%), osteophyte size at the medial femur (66%) and cruciate ligaments (67%) and cartilage damage at the medial tibia (47%) and femur (75%; n=7, untreated n=6). Paquinimod reduces leukocyte recruitment during sterile inflammation. Paquinimod also reduced priming of proinflammatory effector CD4(+) T cells. | [Biological Activity]
Paquinimod (ABR-215757) is an orally active quinoline-3-carboxamide (Q substance) class immunomodulator th at targets S100A9 (Calgranulin B; MRP14) via direct binding and blocks its interaction with receptor for advanced glycation end products (RAGE) and Toll-like receptor 4 (IC50 = 26 μM & 23 μM against 100 nM hS100A9 from binding immobilized hRAGE & hTLR4/MD2respectively). Paquinimod in vivo efficacy is demonstrated in murine models of autoimmune/inflammatory diseasesincluding liver fibrosiscollagen-induced osteoarthritisperitonitisEAEtype 1 diabeteslupus (0.04-25 mg/kg/day p.o.)and atherosclerosis (10 mg/kg i.p.). | [Synthesis]
1. 5-Ethyl-4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid methyl ester (5.00 g) was dissolved in n-heptane (200 mL) with N-ethylaniline (4.7 g), 4A molecular sieves (22.9 g) were added and placed in a Soxhlet extraction device under reflux.
2. After refluxing for 2.0 hours the heating was stopped and the reaction mixture was cooled to room temperature.
3. The crystalline suspension in the reaction mixture was filtered and the solid product was collected.
4. The precipitate was washed with n-heptane and subsequently dried under vacuum to afford N-ethyl-N-phenyl-5-ethyl-1,2-dihydro-4-hydroxy-1-methyl-2-oxoquinoline-3-carboxamide (A) in a yield of 5.53 g (82% yield).
5. The isolated product was analyzed by 1H-NMR and was shown to contain 2% unreacted ester. 1H-NMR (d-DMSO) data were as follows: broad peaks appeared at 11.1 (1H), 7.41 (1H), 7.29 (2H), 7.21 (3H), 7.14 (1H), 6.96 (1H), 3.80 (2H), 3.42 (3H), 3.08 ( 2H), 1.07 (3H) ppm.
6. According to U.S. Patent No. 6,875,869, a 2 hour reaction from n-heptane by conventional distillation under the same reaction conditions resulted in a product yield of 85% (based on Compound A). 1H-NMR analysis showed the product to be a mixture of Compound A (75 mol%) and the feedstock ester (25 mol%). | [in vivo]
S100A9 is a calcium-binding protein of the S100 family. Paquinimod is an immunomodulatory compound preventing S100A9 binding to TLR-4. Prophylactic treatment with S100A9 inhibitor Paquinimod reduces pathology in experimental collagenase-induced osteoarthritis[1]. Paquinimod is a potent inhibitor of insulitis and diabetes development in the NOD mouse. To assess the preventive efficacy of Paquinimod on diabetes development in female NOD mice, groups of mice are treated with daily doses of 0.04, 0.2, 1, and 5 mg/kg/day of Paquinimod from week 10 of age until week 20 of age. Glycosuria is analyzed on a weekly basis from 10 weeks of age until the endpoint of the experiment at 40 weeks of age. There is a clear dose-dependent reduction in diabetes development in the Paquinimod-treated mice[2]. | [References]
[1] Patent: WO2012/4338, 2012, A1. Location in patent: Page/Page column 13; 15 |
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