A-205804 - CAS 251992-66-2
Catalog number: 251992-66-2
Category: Inhibitor
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Molecular Formula:
C15H12N2OS2
Molecular Weight:
300.4
COA:
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Targets:
E-selectin
Description:
A-205804 is a potent and selective inhibitor of E-selectin and ICAM-1 expression with IC50 of 20 nM and 25 nM respectively.
Purity:
>98%
Synonyms:
A-205804
MSDS:
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InChIKey:
QQGWEXFLMJGCAL-UHFFFAOYSA-N
InChI:
InChI=1S/C15H12N2OS2/c1-9-2-4-10(5-3-9)19-13-7-17-8-14-11(13)6-12(20-14)15(16)18/h2-8H,1H3,(H2,16,18)
Canonical SMILES:
CC1=CC=C(C=C1)SC2=C3C=C(SC3=CN=C2)C(=O)N
1.Selective inhibition of ICAM-1 and E-selectin expression in human endothelial cells. 2. Aryl modifications of 4-(aryloxy)thieno[2,3-c]pyridines with fine-tuning at C-2 carbamides.
Zhu GD;Arendsen DL;Gunawardana IW;Boyd SA;Stewart AO;Fry DG;Cool BL;Kifle L;Schaefer V;Meuth J;Marsh KC;Kempf-Grote AJ;Kilgannon P;Gallatin WM;Okasinski GF J Med Chem. 2001 Oct 11;44(21):3469-87.
The elevated expression of cell adhesion molecules (CAMs) on the lumenal surface of vascular endothelial cells is a critical early event in the complex inflammatory process. The adhesive interactions of these CAMs that include E-selectin, ICAM-1, and VCAM-1 with their counter-receptors on leukocytes, such as integrins of the alpha(L)beta(2) family, result in migration of the leukocytes to the site of inflammation and cause tissue injury. Pharmaceutical agents that could suppress the induced expression of one or more of these cell adhesion molecules would provide a novel mechanism to attenuate the inflammatory responses associated with chronic inflammatory diseases. A-205804 (1), a potent and selective inhibitor of the induced expression of E-selectin and ICAM-1 over VCAM-1, was further modified with emphasis at the C-4 and C-2 positions to identify a more potent drug candidate with a good pharmacokinetic profile and physical properties. Replacement of the C-4 sulfur linkage in 1 with an oxygen atom eliminated one of the two major metabolites for this lead molecule. The para-position of the 4-phenoxy group of the thieno[2,3-c]pyridine lead is found to be very critical for a higher in vitro potency and selectivity of E-selectin and ICAM-1 over VCAM-1 expression.
2.Synthesis and mode of action of (125)I- and (3)H-labeled thieno[2,3-c]pyridine antagonists of cell adhesion molecule expression.
Zhu GD;Schaefer V;Boyd SA;Okasinski GF J Org Chem. 2002 Feb 8;67(3):943-8.
A series of thieno[2,3-c]pyridine antagonists of cell adhesion molecule (CAM) expression, such as A-205804 (1) and A-249377 (2), selectively suppressed the induced expression of E-selectin and ICAM-1 over VCAM-1. In an effort to explore the biological mechanism of action of these inhibitors, we synthesized (125)I- and (3)H-labeled thieno[2,3-c]pyridines 5 and 6. An isolated diazonium tetrafluoroborate salt efficiently trapped Na(125)I on very small scale (7.5 microg of Na(125)I), providing the corresponding (125)I-labeled thieno[2,3-c]pyridine in modest yield. Preliminary mechanistic investigations using these radiolabeled compounds revealed that, upon incubation with human umbilical vein endothelial cells (HUVECs), these inhibitors of CAM expression translocated to the cell nucleus and were noncovalently associated with macromolecules of molecular weight greater than 650 kDa.
3.Discovery of inhibitors of cell adhesion molecule expression in human endothelial cells. 1. Selective inhibition of ICAM-1 and E-selectin expression.
Stewart AO;Bhatia PA;McCarty CM;Patel MV;Staeger MA;Arendsen DL;Gunawardana IW;Melcher LM;Zhu GD;Boyd SA;Fry DG;Cool BL;Kifle L;Lartey K;Marsh KC;Kempf-Grote AJ;Kilgannon P;Wisdom W;Meyer J;Gallatin WM;Okasinski GF J Med Chem. 2001 Mar 15;44(6):988-1002.
A critical early event in the inflammatory cascade is the induced expression of cell adhesion molecules on the lumenal surface of vascular endothelial cells. These adhesion molecules include E-selectin, ICAM-1, and VCAM-1, which serve to recruit circulating leukocytes to the site of the inflammation. These adhesive interactions allow the leukocytes to firmly adhere to and cross the vascular endothelium and migrate to the site of tissue injury. Pharmaceutical agents which would prevent the induced expression of one or more of the cell adhesion molecules on the endothelium might be expected to provide a novel mechanism to attenuate the inflammatory responses associated with chronic inflammatory diseases. A thieno[2,3-d]pyrimidine, A-155918, was identified from a whole-cell high-throughput assay for compounds which inhibited the tumor necrosis factor-alpha (TNFalpha)-induced expression of E-selectin, ICAM-1, or VCAM-1 on human vascular endothelial cells. Traditional medicinal chemistry methods were applied to this low-micromolar inhibitor, resulting in the 2,4-disubstituted thieno[2,3-c]pyridine A-205804, a potent and selective lead inhibitor of E-selectin and ICAM-1 expression (IC(50) = 20 and 25 nM, respectively).
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CAS 251992-66-2 A-205804

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