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Results for “Integrin alpha4beta1”

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At least 397 records · Page 22Linked to original sources
PubMed1997

Anti-VLA-4 antibody reduces intimal hyperplasia in the endarterectomized carotid artery in nonhuman primates.

PURPOSE: Recently, very late antigen-4 (VLA-4) has been shown to mediate initial monocyte adhesion and migration to the injured artery. We hypothesized that blocking monocyte adhesion using a specific monoclonal antibody against VLA-4 may reduce intimal hyperplasia. METHODS: Bilateral carotid endarterectomies were performed in eight adult baboons. Among them, five animals received an intravenous bolus injection of anti-VLA-4 antibody (3 mg/kg) during surgery and again after 2 weeks. Three animals underwent bilateral carotid endarterectomies and served as untreated control subjects. Specimens were harvested at 4 weeks and subjected to morphometric analysis, cell proliferation assay, and immunostaining for macrophages. RESULTS: All of the endarterectomized arteries were patent except for one in the treated group. The number of macrophages in the intimal tissues was significantly reduced in the treated arteries compared with that in the control vessels (15.78 +/- 3.05 cells/section versus 33.50 +/- 6.13 cells/section; p < 0.001). The cell proliferation rate was significantly lower (p < 0.001) in the treated vessels (2.88% +/- 1.07%) compared with the control vessels (4.89% +/- 0.77%). The intimal area at the endarterectomized sites of carotid arteries was significantly less (p < 0.05) in the group treated with the anti-VLA-4 antibody (1.10 +/- 0.68 mm2) than in the control group (2.00 +/- 0.52 mm2). CONCLUSION: These data show that blocking monocyte adhesion by use of an anti-VLA-4 antibody significantly reduces the number of intimal macrophages, intimal cell proliferation, and intimal hyperplasia in injured carotid arteries in baboons. This study supports a central role for macrophages in the development of intimal hyperplasia and may suggest a new therapeutic strategy to prevent clinical restenosis.

Animals↗
PubMed1999

Effects of antioxidant enzyme overexpression on the invasive phenotype of hamster cheek pouch carcinoma cells.

To examine the role of reactive oxygen species on the invasive phenotype of cancer cells, we overexpressed manganese- and copper-zinc-containing superoxide dismutases (MnSOD, CuZnSOD) and catalase (Cat) in hamster cheek pouch carcinoma (HCPC-1) cells in vitro using adenoviral vector-mediated gene transfer. Hamster cheek pouch carcinoma cells were transduced with these adenoviral vector constructs alone, or in combination, at concentrations [i.e., multiplicity of infectivity (MOI)] of 100 MOI each. The Escherichia coli beta-galactosidase reporter construct was used as a control virus. Protein expression was examined by Western blot analysis and enzymatic activities were measured using spectrophotometry. To observe the effects of transgene overexpression on in vitro tumor cell invasion, we used the membrane invasion culture system, an accurate and reliable method for examining tumor cell invasion, in vitro. This assay measures the ability of tumor cells to invade a basement membrane matrix consisting of type IV collagen, laminin, and gelatin. MnSOD overexpression resulted in a 50% increase in HCPC-1 cell invasiveness (p < .001); co-overexpression of MnSOD with Cat partially inhibited this effect (p < .05). Moreover, co-overexpression of both SODs resulted in a significant increase in invasiveness compared with the parental HCPC-1 cells (p < .05). These changes could not be correlated with the 72 kDa collagenase IV or stromolysin activities using zymography, or the downregulation of the adhesion molecules E-cadherin or the alpha4 subunit of the alpha4beta1 integrin. These results suggest that hydrogen peroxide may play a role in the process of tumor cell invasion, but that the process does not rely on changes in matrix metalloproteinase activity in the cells, or the expression of cell adhesion molecules.

Adenoviridae↗
PubMed2001

Therapeutic intervention with inhibitors of co-stimulatory pathways in autoimmune disease.

Many humanized antibodies and fusion proteins targeting T-cell co-stimulatory molecules are now in late-stage clinical development (phase II, phase III) or have recently completed phase III clinical trials. Both Amevive, an LFA-3-Ig fusion protein targeting CD2, and Xanelim, a humanized anti-CD11a antibody, have shown efficacy in pivotal phase III trials in patients with plaque psoriasis. These new medicines are poised to enter clinical use in 2002.

Antibodies, Monoclonal↗
PubMed2000

N-benzylpyroglutamyl-L-phenylalanine derivatives as VCAM/VLA-4 antagonists.

A series of N-(N-benzylpyroglutamyl)-4-substituted-L-phenylalanine derivatives was prepared as VLA-4/VCAM antagonists. Analogues substituted by electron deficient benzoylamino groups bearing bulky ortho substituents had low-nM potency in an ELISA assay and low-microM activity in a cell based assay.

Cell Line↗
PubMed2000

Carbacyclic peptide mimetics as VCAM-VLA-4 antagonists.

Substitution of carbon for sulfur in a potent 13-membered cyclic disulfide containing peptide was accomplished via an intramolecular Wittig reaction and resulted in a series of 'carba' analogues. Potency in the VCAM-VLA-4 assay was sensitive to ring size and lower than that of the parent disulfide.

Integrin alpha4beta1↗
PubMed2000

Cyclic thioether peptide mimetics as VCAM-VLA-4 antagonists.

Selective substitution of a sulfur atom by carbon in a highly potent 13-membered cyclic disulfide was accomplished by intramolecular displacement of a bromide. The potency of the resulting thioethers in the VCAM/VLA-4 assay was dependent on ring size and the position of the sulfur atom.

Integrin alpha4beta1↗
PubMed2001

Nitrobenzene compounds inhibit expression of VCAM-1.

A series of nitrobenzene compounds has been discovered as potent inhibitors of VCAM-1 expression and, therefore, potential drug candidates for autoimmune and allergic inflammatory diseases. Structure-activity relationship (SAR) studies showed that a nitro group and two other electron-withdrawing groups are essential for these compounds to be potent inhibitors of VCAM-1 expression.

Autoimmune Diseases↗
PubMed2001

Isoxazolyl, oxazolyl, and thiazolylpropionic acid derivatives as potent alpha(4)beta(1) integrin antagonists.

A series of isoxazolyl, oxazolyl, and thiazolylpropionic acid derivatives derived from LDV was found to be a potent antagonist of the alpha(4)beta(1) integrin. The synthesis and SAR leading up to 3-[3-(1-[-[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino]-3-methyl-butyl)-isoxazol-5-yl]-propionic acid (22) are reported. In an allergic mouse model, compound 22 was efficacious delivered systemically (58% inhib @ 10 mg/kg, sc) as well as by intra-tracheal instillation (ED(50)=2 microg/kg).

Animals↗
PubMed2001

The discovery of sulfonylated dipeptides as potent VLA-4 antagonists.

Directed screening of a carboxylic acid-containing combinatorial library led to the discovery of potent inhibitors of the integrin VLA-4. Subsequent optimization by solid-phase synthesis afforded a series of sulfonylated dipeptide inhibitors with structural components that when combined in a single hybrid molecule gave a sub-nanomolar inhibitor as a lead for medicinal chemistry. Preliminary metabolic studies led to the discovery of substituted biphenyl derivatives with low picomolar activities. SAR and pharmacokinetic characterization of this series are presented.

Animals↗
PubMed2001

Discovery and evaluation of piperidinyl carboxylic acid derivatives as potent alpha(4)beta(1) integrin antagonists.

Piperidinyl carboxylic acid-based derivatives were prepared as antagonists of the leukocyte cell adhesion process that is mediated through the interaction of the alpha(4)beta(1) integrin (VLA-4, very late antigen 4) and the vascular cell adhesion molecule 1 (VCAM-1). Compounds 2a-h inhibited the adhesion in a cell-based assay in the low and sub micromolar range, a pharmacokinetic study of 2d is reported.

Area Under Curve↗
PubMed2002

Specific and dual antagonists of alpha(4)beta(1) and alpha(4)beta(7) integrins.

N-(3,5-Dichlorophenylsulfonyl)-(R)-thioprolyl biarylalanine 10a has been identified as a potent and specific antagonist of the alpha(4)beta(1) integrin. Altering the configuration of thioproline from R to S led to a series of dual antagonists of alpha(4)beta(1) and alpha(4)beta(7), and the N-acetyl analogue 8b was found to be the most potent dual antagonist. A binding site model for alpha(4)beta(1) and alpha(4)beta(7) is proposed to explain the structure-activity relationship.

Alanine↗
PubMed2002

The discovery of small molecule carbamates as potent dual alpha(4)beta(1)/alpha(4)beta(7) integrin antagonists.

The alpha(4)beta(1) and alpha(4)beta(7) integrins are implicated in several inflammatory disease states. Systematic SAR studies of an alpha(4)beta(1)-specific arylsulfonyl-Pro-Tyr lead led to the identification of a new alpha(4)beta(7) binding site, best captured by O-carbamates of Tyr for this structural class. Several compounds showed a 200- to 400-fold improvement in alpha(4)beta(7) binding affinity while maintaining subnanomolar alpha(4)beta(1) activity, for example 2l, VCAM-Ig alpha(4)beta(1) IC(50)=0.13 nM, VCAM-Ig alpha(4)beta(7) IC(50)=1.92 nM.

Carbamates↗
PubMed2002

N-acyl-L-phenylalanine derivatives as potent VLA-4 antagonists that mimic a cyclic peptide conformation.

A series of N-benzylpyroglutamyl-L-phenylalanine derivatives bearing carbamoyl substituents in the 3- or 4-positions was prepared and assayed for inhibition of the interaction between VCAM and VLA-4. Potent inhibition was observed in a number of analogues with substitution in the 4-position favored over the 3-position. A crystal structure of the key intermediate 25 indicates that it accesses a low energy conformation which closely matches key pharmacophores of a structurally characterized cyclic peptide.

Cell Line↗