Substituted tetrahydrofuroyl-1-phenylalanine derivatives as potent and specific VLA-4 antagonists

Doherty, George; Yang, Gee-Gwo; Borges, Edite; Chang, Linda; MacCoss, Malcolm; Tong, Sharon; Kidambi, Usha; Egger, Linda A.; McCauley, Ermenegilda; Riper, Gail Van; Mumford, Richard A.; Schmidt, John A.

doi:10.1016/s0960-894x(02)00211-1

Cited by 18 publications

(9 citation statements)

References 8 publications

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“…In an effort to reduce plasma protein binding and improve the specificity for VLA-4 versus a 4 b 7 , a systematic study of substitution at the a-carbon of the tetrahydrofuran ring was undertaken. 102 The ether analog 34b was equipotent to the methyl compound and had a reduced plasma protein binding. However, this reduction in protein binding also resulted in a significant loss in rat pharmacokinetics (F ¼ 2%; Cl p ¼ 81 ml/kg/min).…”

Section: N-acylphenylalanine Derivativesmentioning

confidence: 99%

VLA‐4 antagonists: Potent inhibitors of lymphocyte migration

Yang

Hagmann

2003

Medicinal Research Reviews

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Circulating lymphocytes normally migrate through extravascular spaces in relatively low numbers as important members of the immunosurveillance process. That is until signals are received by endothelial cells that there is an underlying infection or inflammatory condition. These vascular surface cells in turn overexpress and present ligands to circulating lymphocyte adhesion molecules. Upon encountering this higher density of ligands, lymphocytes, which had been leisurely rolling along the vascular surface, now become more firmly attached, change shape, and migrate through tight junctions to the sites of infection or inflammation. If the initiating events are not resolved and the condition becomes chronic, there can be a sustained extravasation of lymphocytes that can exacerbate the inflammatory condition, which in turn will continue to recruit more inflammatory cells resulting in unwanted tissue destruction. It is for the attenuation of this cycle of sustained inflammatory cell recruitment that very late activating antigen-4 (VLA-4) antagonists are being developed. Most lymphocytes, except neutrophils, express VLA-4 on their surface and they interact with endothelial vascular cell adhesion molecule-1 (VCAM-1). It is this interaction that VLA-4 antagonists are intended to disrupt, thus, putting an end to the cycle of chronic inflammation, which is the hallmark of many diseases. This review will provide an update of VLA-4 antagonists that have appeared since early 2001 and will discuss some of the issues, both positive and negative, that may be encountered in their development.

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Section: N-acylphenylalanine Derivativesmentioning

confidence: 99%

VLA‐4 antagonists: Potent inhibitors of lymphocyte migration

Yang

Hagmann

2003

Medicinal Research Reviews

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“…It is also worthwhile appreciating the synthetic usefulness of this class of γ‐bromolactone 4 . As depicted in Scheme , 1,1‐disubstituted THF system 7 could be obtained in high yield and enantiopurity through a three‐step sequence ( 4a → 5 → 6 → 7 ), for which 7 is the advanced synthetic intermediate of VLA‐4 antagonists 8 …”

Section: Thiocarbamate and Carbamate Catalystsmentioning

confidence: 99%

Lewis Base Catalyzed Stereo‐ and Regioselective Bromocyclization

Gieuw

Yeung

2016

The Chemical Record

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Oxygen- and nitrogen-containing heterocyclic compounds are widely recognized as key components in many natural products and biologically relevant molecules, but often the problem comes down to methodologies in synthesizing them. Halocyclization of olefinic substrates is a promising strategy in the construction of O- and N-heterocyclic compounds, which further signifies the development of their asymmetric variants. Over the past years, our group has been devoted to this particular area of asymmetric electrophilic halocyclization with chalcogen-containing molecules as catalysts. In this account, the main focus is on the development of our novel chiral catalysts and applications derived from the reaction products.

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“…The products of bromolactonization are useful for transformation into higher‐value intermediates. For example, γ‐lactone 4b could be subjected into a three‐step transformation into 24 , which is a precursor of the VLA‐4 antagonist (Scheme ) …”

Section: Challenges Of Developing Enantioselective Bromocyclization Omentioning

confidence: 99%

Stereoselective Bromofunctionalization of Alkenes

Tan

Yeung

2013

Chirality

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The stereoselective bromofunctionalization of alkenes, particularly the enantioselective format, has been a subject of intense research in recent years. The ground-breaking works are documented in recent reviews. On the other hand, this account will provide an insight into our group's approach in tackling the challenges in enantioselective bromocyclization of alkenes as well as the development of diastereoselective N-bromosuccinimide-initiated multicomponent reactions.

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Substituted tetrahydrofuroyl-1-phenylalanine derivatives as potent and specific VLA-4 antagonists

Cited by 18 publications

References 8 publications

VLA‐4 antagonists: Potent inhibitors of lymphocyte migration

VLA‐4 antagonists: Potent inhibitors of lymphocyte migration

Lewis Base Catalyzed Stereo‐ and Regioselective Bromocyclization

Stereoselective Bromofunctionalization of Alkenes

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