Novel Synthetic Inhibitors of Selectin-Mediated Cell Adhesion:  Synthesis of 1,6-Bis[3-(3-carboxymethylphenyl)-4-(2-α-<scp>d</scp>-mannopyranosyloxy)phenyl]hexane (TBC1269)

Kogan, Timothy P.; Dupre, Brian; Bui, Huong Thi; McAbee, Kathy L.; Kassir, Jamal M.; Scott, Ian L.; Hu, Xin; Vanderslice, Peter; Beck, Pamela J.; Dixon, Richard A. F.

doi:10.1021/jm9704917

Cited by 126 publications

(94 citation statements)

References 32 publications

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“…The specific inhibitors of p38 MAPK (SB-202190) and p42/44 MAPK (PD98059) were purchased from Biomol Research Laboratories (Plymouth Meeting, PA). The sialyl diLewis x mimetic inhibitor TBC 1269 (1,6-Bis[3-(3-carboxymethylphenyl)-4-(2-␣-D-mannopyranosyloxy)phenyl]hexane) and the control compound TBC 1900 were gifts from Texas Biotechnology (Houston, TX) (26). PEconjugated anti-human Mac-1 (2LPM19c) was purchased from DAKO (Carpinteria, CA).…”

Section: Agonists Inhibitors and Absmentioning

confidence: 99%

Shear-Dependent Capping of L-Selectin and P-Selectin Glycoprotein Ligand 1 by E-Selectin Signals Activation of High-Avidity β2-Integrin on Neutrophils

Green

Pearson

Camphausen³

et al. 2004

The Journal of Immunology

116

129

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Two adhesive events critical to efficient recruitment of neutrophils at vascular sites of inflammation are up-regulation of endothelial selectins that bind sialyl Lewisx ligands and activation of β2-integrins that support neutrophil arrest by binding ICAM-1. We have previously reported that neutrophils rolling on E-selectin are sufficient for signaling cell arrest through β2-integrin binding of ICAM-1 in a process dependent upon ligation of L-selectin and P-selectin glycoprotein ligand 1 (PSGL-1). Unresolved are the spatial and temporal events that occur as E-selectin binds to human neutrophils and dynamically signals the transition from neutrophil rolling to arrest. Here we show that binding of E-selectin to sialyl Lewisx on L-selectin and PSGL-1 drives their colocalization into membrane caps at the trailing edge of neutrophils rolling on HUVECs and on an L-cell monolayer coexpressing E-selectin and ICAM-1. Likewise, binding of recombinant E-selectin to PMNs in suspension also elicited coclustering of L-selectin and PSGL-1 that was signaled via mitogen-activated protein kinase. Binding of recombinant E-selectin signaled activation of β2-integrin to high-avidity clusters and elicited efficient neutrophil capture of β2-integrin ligands in shear flow. Inhibition of p38 and p42/44 mitogen-activated protein kinase blocked the cocapping of L-selectin and PSGL-1 and the subsequent clustering of high-affinity β2-integrin. Taken together, the data suggest that E-selectin is unique among selectins in its capacity for clustering sialylated ligands and transducing signals leading to neutrophil arrest in shear flow.

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Section: Agonists Inhibitors and Absmentioning

confidence: 99%

Shear-Dependent Capping of L-Selectin and P-Selectin Glycoprotein Ligand 1 by E-Selectin Signals Activation of High-Avidity β2-Integrin on Neutrophils

Green

Pearson

Camphausen³

et al. 2004

The Journal of Immunology

116

129

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“…16,17 This inhibitor inhibits binding of E-, P-, and L-selectins to sLe x , with inhibitory concentration 50 (IC 50 ) values of 105 µM, 17 µM, and 87 µM, respectively. 16 Results of safety and efficacy studies indicate that TBC1269 does not have cytotoxic effects. 16 TBC1269 has been used in humans with allergic asthma.…”

Section: Preparation Of Tbc1269-tbc1269mentioning

confidence: 99%

“…16 Results of safety and efficacy studies indicate that TBC1269 does not have cytotoxic effects. 16 TBC1269 has been used in humans with allergic asthma. Treatment resulted in a reduction in number of eosinophils in sputum and improvement of the late bronchoconstriction reaction.…”

Section: Preparation Of Tbc1269-tbc1269mentioning

confidence: 99%

“…A small molecule synthetic selectin inhibitor, TBC1269, has been shown to inhibit sLe x -dependent binding and binding of leukocytes to P-, E-, and Lselectin in vitro. 16,17 This compound has also been tested in sheep with experimentally induced allergic pulmonary disease. Treatment with TBC1269 resulted in significant protection against allergic airway responses.…”

mentioning

confidence: 99%

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Effects of the synthetic selectin inhibitor TBC1269 on tissue damage during acute Mannheimia haemolytica-induced pneumonia in neonatal calves

Radi¹,

Caverly²,

Dixon³

et al. 2001

ajvr

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Objective—To determine effects of the selectin inhibitor TBC1269 on neutrophil-mediated pulmonary damage during acute Mannheimia haemolytica-induced pneumonia in newborn calves. Animals—Eighteen 1- to 3-day-old colostrumdeprived calves. Procedure—Mannheimia haemolytica or saline (0.9% NaCl) solution was inoculated in both cranial lung lobes of 12 and 6 calves, respectively. Calves were euthanatized 2 (saline, n = 3; M haemolytica, n = 4) or 6 hours (saline, n = 3; M haemolytica, n = 8) after inoculation. Four M haemolytica-inoculated calves euthanatized at 6 hours also received TBC1269 (25 mg/kg, IV) 30 minutes before and 2 hours after inoculation. Conjugated diene (CD) concentrations, inducible nitric oxide synthase (iNOS) expression, and apoptotic cell counts were determined in lung specimens collected during necropsy. Results—Conjugated diene concentrations were significantly increased in all M haemolytica-inoculated groups, compared with saline-inoculated groups. Calves treated with TBC1269 had decreased concentrations of CD, compared with untreated calves, although the difference was not significant. Number of apoptotic neutrophils and macrophages increased significantly in TBC1269-treated calves, compared with untreated calves. Inducible nitric oxide synthase was expressed by epithelial cells and leukocytes. However, iNOS was less abundant in airway epithelial cells associated with inflammatory exudates. Degree of iNOS expression was similar between TBC1269-treated and untreated calves. Conclusions—Mannheimia haemolytica infection in neonatal calves resulted in pulmonary tissue damage and decreased epithelial cell iNOS expression. The selectin inhibitor TCB1269 altered, but did not completely inhibit, neutrophil-mediated pulmonary damage. ( Am J Vet Res 2001;62:17–22)

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“…binding of sialyl Lewis X to selectins in vitro. [22][23][24][25] This mimetic has been used in vivo in clinical studies for use in the treatment of humans with allergic asthma. It is effective for preventing neutrophil-mediated reperfusion injury in rat liver 23 and in reducing the initial cellular response to pulmonary antigen in a sheep model of allergic bronchoconstriction.…”

mentioning

confidence: 99%

Comparison of bronchoalveolar lavage fluid obtained from Mannheimia haemolytica-inoculated calves with and without prior treatment with the selectin inhibitor TBC1269

Caverly¹,

Radi²,

Andreasen³

et al. 2001

ajvr

Self Cite

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Objectives—To determine effects of selectin inhibitor TBC1269 on neutrophil infiltration, and neutrophilassociated injury during pneumonia induced by Mannheimia haemolytica and concentration of antimicrobial anionic peptide (AAP) in bronchoalveolar lavage fluid (BALF) as well as antimicrobial activity of BALF from healthy (control) neonatal calves, neonatal calves with M haemolytica-induced pneumonia, neonatal calves with prior treatment with TBC1269, and adult cattle. Animals—Eighteen 1- to 3-day-old calves and 9 adult cattle. Procedure—Calves were inoculated with M haemolyticaor pyrogen-free saline (0.14M NaCl) solution into the right cranial lung lobe, and BALF was collected 2 or 6 hours after inoculation. Thirty minutes before and 2 hours after inoculation, 4 calves received TBC1269. The BALF collected from 9 adult cattle was used for comparison of BALF AAP concentration and antimicrobial activity. Protein concentration and neutrophil differential percentage and degeneration in BALF were determined. An ELISA and killing assay were used to determine BALF AAP concentration and antimicrobial activity, respectively. Results—Total protein concentration was significantly decreased in BALF from calves receiving TBC1269. Similar concentrations of AAP were detected in BALF from all calves, which were 3-fold higher than those in BALF from adult cattle. However, BALF from neonates had little or no anti-M haemolytica activity. Conclusions and Clinical Relevance—These results suggest that TBC1269 decreases pulmonary tissue injury in neonatal calves infected with M haemolytica. Although AAP is detectable in neonatal BALF at 3 times the concentration detected in adult BALF, neonatal BALF lacks antimicrobial activity for M haemolytica. (Am J Vet Res 2001;62:665–672)

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Novel Synthetic Inhibitors of Selectin-Mediated Cell Adhesion: Synthesis of 1,6-Bis[3-(3-carboxymethylphenyl)-4-(2-α-d-mannopyranosyloxy)phenyl]hexane (TBC1269)

Cited by 126 publications

References 32 publications

Shear-Dependent Capping of L-Selectin and P-Selectin Glycoprotein Ligand 1 by E-Selectin Signals Activation of High-Avidity β2-Integrin on Neutrophils

Shear-Dependent Capping of L-Selectin and P-Selectin Glycoprotein Ligand 1 by E-Selectin Signals Activation of High-Avidity β2-Integrin on Neutrophils

Effects of the synthetic selectin inhibitor TBC1269 on tissue damage during acute Mannheimia haemolytica-induced pneumonia in neonatal calves

Comparison of bronchoalveolar lavage fluid obtained from Mannheimia haemolytica-inoculated calves with and without prior treatment with the selectin inhibitor TBC1269

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