The design and synthesis of potent cyclic peptide VCAM–VLA-4 antagonists incorporating an achiral Asp-Pro mimetic

Fotouhi, Nader; Joshi, Pramod V.; Fry, David C.; Cook, Charles M.; Tilley, Jefferson; Kaplan, Gerry; Hanglow, A. C.; Rowan, Karen; Schwinge, Virginia; Wolitzky, Barry A.

doi:10.1016/s0960-894x(00)00174-8

Cited by 19 publications

(8 citation statements)

References 2 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In the case of cesium carbonate, the reactions were clean and efficient. Importantly, in the present protocol the dialkylation reaction is free from any side product formation, such as monoalkylated product [14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33] , O-alkylation 30 and condensation product. Bases like sodium ethoxide, potassium tert-butoxide, potassium phosphate and sodium hydride are known to give rise to considerable O-alkylation in DMF.…”

Section: Resultsmentioning

confidence: 99%

Cesium carbonate mediated exclusive dialkylation of active methylene compounds

Sankar¹,

Raju²,

Uma³

2012

CCL

View full text Add to dashboard Cite

show abstract

Section: Resultsmentioning

confidence: 99%

Cesium carbonate mediated exclusive dialkylation of active methylene compounds

Sankar¹,

Raju²,

Uma³

2012

CCL

View full text Add to dashboard Cite

show abstract

“…Although a loss of activity was observed when Asp-Pro were simultaneously replaced in the cyclic peptides, 53 the possibility of a replacement of the Asp-Pro moiety was investigated. 54 An NMR-based conformation model of 2a was used as a starting point and each potential spacer was computed using the molecular modeling package Sybyl TM . Based on the modeling results, a series of compounds were then synthesized.…”

Section: V L a -4 A N T A G O N I S T S A Cyclic Peptidesmentioning

confidence: 99%

VLA‐4 antagonists: Potent inhibitors of lymphocyte migration

Yang

Hagmann

2003

Medicinal Research Reviews

View full text Add to dashboard Cite

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.

show abstract

“…Remarkably, not only was the backbone rigidly constrained, but the thioproline residue was fixed completely in the cis conformation. A series of peptide analogs was designed in which the AspthiaPro portion was replaced with 1-(2-aminoethyl)cyclopentyl-carboxylic acid, and no loss of potency resulted [61]. By using NMR-derived structural information from the peptides, non-peptidic small molecule inhibitors were developed, based on a N-benzylpyro-glutamyl-phenylalanine core [62].…”

Section: Integrinsmentioning

confidence: 99%

Utilizing Peptide Structures As Keys For Unlocking Challenging Targets

Fry¹,

Sun²

2006

MRMC

Self Cite

View full text Add to dashboard Cite

Three-dimensional structures of protein targets have proven to be extremely valuable for modern drug design and discovery. For cases where the structure of the protein is unattainable, such as G-protein coupled receptors (GPCRs), structural information on active ligands is still useful and helpful for deciphering the geometrical and chemical features of the active site. Peptides, constructed from easy-to-form amide backbones and featuring variable side-chains, have an inherent advantage in generating rapid quantitative structure-activity relationships (QSAR). Given the fact that peptides are natural ligands for many protein targets, structural investigation of a series of related peptides, typically carried out via nuclear magnetic resonance (NMR), can result in an accurate pharmacophore model. Such a model can be used for virtual screening, and to assist design of second-generation peptidomimetics with improved properties and design of non-peptidic leads. In this article, we will review examples in which a structural approach utilizing peptide ligands was employed to obtain a better understanding of the target active site. We will focus on cases where such information supplied guidance toward the discovery of small molecule ligands.

show abstract

The design and synthesis of potent cyclic peptide VCAM–VLA-4 antagonists incorporating an achiral Asp-Pro mimetic

Cited by 19 publications

References 2 publications

Cesium carbonate mediated exclusive dialkylation of active methylene compounds

Cesium carbonate mediated exclusive dialkylation of active methylene compounds

VLA‐4 antagonists: Potent inhibitors of lymphocyte migration

Utilizing Peptide Structures As Keys For Unlocking Challenging Targets

Contact Info

Product

Resources

About