Synthesis and Biological Evaluation of Novel Pyridazinone-Based α<sub>4</sub>Integrin Receptor Antagonists

Gong, Yong; Jk, Barbay; Ab, Dyatkin; Ta, Miskowski; Es, Kimball; Sm, Prouty; Fisher, Matthew C.; Rj, Santulli; Schneider, Christian; Nh, Wallace; Sa, Ballentine; We, Hageman; Ja, Masucci; Be, Maryanoff; Bp, Damiano; Andrade‐Gordon, Patricia; Dj, Hlasta; Pj, Hornby; He, Wenbo

doi:10.1021/jm060031q

Cited by 36 publications

(17 citation statements)

References 27 publications

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“…Preclinical animal model Drug mechanism Drug Clinical trial Phase a IBD Adhesion molecules integrin α 4 β 7 DSS (Gong et al, 2006) Humanized mAb anti α 4 β 7 integrin Vedolizumab III UC/CD MAdCAM-1 TNBS (Goto et al, 2006) Antisense oligonucleotide Natalizumab III/IV CD ICAM-1 DSS (Hamamoto et al, 1999) Antisense oligonucleotide Alicaforsen III CD ICAM-1/E-Selectin DSS (Panes et al, 2007) Inhibitor of adhesion molecule expression GI270384X I UC…”

Section: Targetmentioning

confidence: 99%

Animal models of chemically induced intestinal inflammation: Predictivity and ethical issues

Dothel

Vasina

Barbara

et al. 2013

Pharmacology & Therapeutics

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Section: Targetmentioning

confidence: 99%

Animal models of chemically induced intestinal inflammation: Predictivity and ethical issues

Dothel

Vasina

Barbara

et al. 2013

Pharmacology & Therapeutics

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“…Treatment with this antibody also reduced the colonic infiltration of leukocytes. In another animal model of induced colitis, the dextran sodium sulfate (DSS)-colitic mouse, a pyridazinone-based a 4 b 7 selective antagonist demonstrated oral in-vivo activity [Gong et al 2006].…”

Section: Approaches To Targeting Adhesion Molecules and Their Associamentioning

confidence: 99%

Review: Anti-adhesion molecule therapy for inflammatory bowel disease

Ghosh

Panaccione

2010

Therap Adv Gastroenterol

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Although biologic agents directed against tumor necrosis factor alpha (TNFa) continue to be an effective therapeutic strategy for patients with inflammatory bowel disease (IBD), approximately 30% of patients with Crohn's disease (CD) who are refractory to standard treatment do not respond to induction therapy with TNFa inhibitors and, of those who initially respond, 50% or more cease to respond within a year. Moreover, their use can be associated with significant safety issues. Clearly, there is a need to target alternative pathways involved in the inflammatory process. IBD is driven by the trafficking of lymphocytes from the circulation into the gut tissue that is mediated by adhesive interactions between the lymphocytes and endothelial cells. The adhesion molecules involved represent attractive targets for the development of new therapeutics which should aid in the resolution of existing inflammation, prevent recurrence of inflammation, and may potentially lead to long-term control of disease. In this article we review current opportunities and challenges facing anti-adhesion therapy in IBD, and discusses recent clinical development efforts that have focused on having an impact on two particular adhesive interactions: a 4 -integrin/MAdCAM-1 and b 2 -integrin/ICAM-1. Of particular interest is natalizumab, a humanized monoclonal antibody against human a 4 integrin that is approved for the treatment of patients with moderately-to-severely active CD and evidence of active inflammation. This agent represents an efficacious therapeutic option for patients who do not respond to, or have failed, a TNF-a inhibitor.

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“…2C) is described in the literature as a potent ligand that blocks VLA-4 binding to vascular cell adhesion molecule 1 (VCAM-1). 11,16,24 Compounds D and E ( Fig. 2D and 2E) are two novel VLA-4 ligands discovered in a high-throughput screen at the University of New Mexico Center for Molecular Discovery (http://pubchem.ncbi.nlm.nih.gov, AID: 529, 702).…”

Section: Homology Modeling and Dockingmentioning

confidence: 99%

Conformational mAb as a Tool for Integrin Ligand Discovery

Njus

Chigaev

Waller

et al. 2009

ASSAY and Drug Development Technologies

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alpha(4)beta(1)-Integrin (very late antigen-4 (VLA-4)) mediates cell adhesion to cell surface ligands (VCAM-1). Binding of VLA-4 to VCAM-1 initiates rolling and firm adhesion of leukocytes to vascular endothelium followed by the extravasation into the tissue. VLA-4-dependent adhesion plays a key role in controlling leukocyte adhesive events. Small molecules that bind to the integrin ligand-binding site and block its interaction with natural ligands represent promising candidates for treatment of several diseases. Following a flow cytometric screen for small molecule discovery, we took advantage of a conformationally sensitive anti-beta(1)-integrin antibody (HUTS-21) and a small LDV-containing ligand (LDV-FITC) with known affinity to study binding affinities of several known and recently discovered integrin ligands. We found that binding of the LDV-containing small molecule induced exposure of HUTS-21 epitope and that the EC(50) for antibody binding was equal to previously reported K(d) for fluorescent LDV (LDV-FITC). Thus, binding of HUTS-21 can be used to report ligand-binding site occupancy. We studied binding of two known integrin ligands (YLDV and TR14035), as well as of two novel compounds. EC(50) values for HUTS-21 binding showed good correlation with K(i)s determined in the competition assay with LDV-FITC for all ligands. A docking model suggests a common mode of binding for the small molecule VLA-4 ligands. This novel approach described here can be used to determine ligand-binding affinities for unlabeled integrin ligands, and can be adapted to a high-throughput screening format for identification of unknown integrin ligands.

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Synthesis and Biological Evaluation of Novel Pyridazinone-Based α₄Integrin Receptor Antagonists

Cited by 36 publications

References 27 publications

Animal models of chemically induced intestinal inflammation: Predictivity and ethical issues

Animal models of chemically induced intestinal inflammation: Predictivity and ethical issues

Review: Anti-adhesion molecule therapy for inflammatory bowel disease

Conformational mAb as a Tool for Integrin Ligand Discovery

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Synthesis and Biological Evaluation of Novel Pyridazinone-Based α4Integrin Receptor Antagonists

Cited by 36 publications

References 27 publications

Animal models of chemically induced intestinal inflammation: Predictivity and ethical issues

Animal models of chemically induced intestinal inflammation: Predictivity and ethical issues

Review: Anti-adhesion molecule therapy for inflammatory bowel disease

Conformational mAb as a Tool for Integrin Ligand Discovery

Contact Info

Product

Resources

About

Synthesis and Biological Evaluation of Novel Pyridazinone-Based α₄Integrin Receptor Antagonists