Discovery of a potent, orally bioavailable pyrimidine VLA-4 antagonist effective in a sheep asthma model

Semko, Christopher M.; Chen, Linda; Dressen, Darren; Dreyer, Mark; Dunn, Whitney; Farouz, Francine S.; Freedman, Stephen B.; Holsztynska, Elizabeth J.; Jefferies, Michael; Konradi, Andrei W.; Liao, Anna; Lugar, Judevin; Mutter, Linda; Pleiss, Michael A.; Quinn, Kevin P.; Thompson, Thomas N.; Thorsett, Eugene D.; Vandevert, Christopher; Xu, Yinchuan; Yednock, Ted

doi:10.1016/j.bmcl.2011.01.075

Cited by 6 publications

(3 citation statements)

References 10 publications

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“…Earlier small molecule integrin inhibitors have not advanced in the treatment of airway inflammation. Recently, Elan Corporation reported VLA-4 antagonists orally active in sheep asthma model [101].…”

Section: Very Late Antigen-4 (α4β1 Integrin) Antagonistsmentioning

confidence: 99%

Allergic rhinitis: An update on disease, present treatments and future prospects

Mandhane¹,

Shah²,

Thennati³

2011

International Immunopharmacology

110

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Section: Very Late Antigen-4 (α4β1 Integrin) Antagonistsmentioning

confidence: 99%

Allergic rhinitis: An update on disease, present treatments and future prospects

Mandhane¹,

Shah²,

Thennati³

2011

International Immunopharmacology

110

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“…Firategrast (Kawaguchi et al, 2002), developed by Tanabe and GSK, belonging to the same class of compounds, reached phase II trials for MS and is currently studied as a facilitator in the “ in utero ” hematopoietic cell transplantation (IUHCT), a pioneering approach for critical fetal diseases treatment (Kim et al, 2016). By refining the structure of an already reported antagonist α 4 β 1 , the researchers of Elan Pharmaceuticals faced the limited bioavailability of their lead compound, by introducing N -arylated heterocycles to mimic the carboxamide (Semko et al, 2011). This last moiety was indeed considered partially responsible for the poor pharmacokinetic profile.…”

Section: Small Molecules Targeting α4β1 Integrinmentioning

confidence: 99%

Novel Ligands Targeting α4β1 Integrin: Therapeutic Applications and Perspectives

et al. 2019

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Among the other members of the adhesion molecules' family, α 4 β 1 integrin, a heterodimeric receptor, plays a crucial role in inflammatory diseases, cancer development, metastasis and stem cell mobilization or retention. In many cases, its function in pathogenesis is not yet completely understood and investigations on ligand binding and related stabilization of active/inactive conformations still represent an important goal. For this reason, starting from the highlight of α 4 β 1 functions in human pathologies, we report an overview of synthetic α 4 β 1 integrin ligands under development as potential therapeutic agents. The small molecule library that we have selected represents a collection of lead compounds. These molecules are the object of future refinement in academic and industrial research, in order to achieve a fine tuning of α 4 β 1 integrin regulation for the development of novel agents against pathologies still eluding an effective solution.

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“…For example, I‐BET151 (GSK1210151A, 1 ) is widely used as a research tool in epigenetic screening; it is a potent and selective inhibitor of bromodomains BRD2, BRD3 and BRD4 (IC 50 = 0.2–0.8 µ m ) . Other biologically active 4‐hetarylisoxazoles include VLA‐4 antagonist 2 (IC 50 < 1 n m ), cGMP‐specific phosphodiesterase type 5 (PDE5A) inhibitor 3 (IC 50 = 0.36 n m ), or Abelson murine leukemia viral oncogene homolog 1 (ABL1) inhibitor 4 (IC 50 = 0.1 n m ), (Figure )…”

Section: Introductionmentioning

confidence: 99%

Synthesis of 4‐Hetarylisoxazoles from Amino Acid‐Derived Halogenoximes and Push‐Pull Enamines

et al. 2018

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An approach to 4‐hetarylisoxazole‐derived amines and other related 3,4‐disubstituted isoxazoles which relies on [3+2] cycloaddition of amino acid‐derived halogenoximes and push‐pull enamines is described. The target products are obtained at gram scale in up to 81 % overall yield. The efficiency of the method is affected by the electronic properties of the enamine component at the key step.

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Discovery of a potent, orally bioavailable pyrimidine VLA-4 antagonist effective in a sheep asthma model

Cited by 6 publications

References 10 publications

Allergic rhinitis: An update on disease, present treatments and future prospects

Allergic rhinitis: An update on disease, present treatments and future prospects

Novel Ligands Targeting α4β1 Integrin: Therapeutic Applications and Perspectives

Synthesis of 4‐Hetarylisoxazoles from Amino Acid‐Derived Halogenoximes and Push‐Pull Enamines

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