Very late antigen-4 integrin antagonists

Integrins as therapeutic targets: lessons and opportunities

“…In addition, although the success of natalizumab and efalizumab has shown the clinical relevance of the α 4 and α L β 2 integrins, and encouraged the search for smallmolecule antagonists [183][184][185] , the side-effects with both natalizumab and efalizumab could discourage companies from pursuing small-molecule antagonists for these As shown in panel a of the figure, the default conformation of the platelet-specific α IIb β 3 integrin in unactivated platelets is maintained by clasps in the cytoplasmic tails 94 , whereby the integrin α and β cytoplasmic tails form a salt bridge between the highly conserved β-HDRKE motif and the arginine in the α-KVGFFKR motif 188 .…”

Tripeptide Motifs in Biology: Targets for Peptidomimetic Design

“…The 4-biphenylalanine analogue (Figure ) at 80 pM exhibited excellent activity in a VCAM-1 binding assay and also had favorable pharmacokinetic profile. , Many thousands of VCAM-1 antagonists that bind to the LDV site on integrins have been reported in the academic and patent literature in the past decade. A recent review by Tilley summarized small-molecule α4 integrin antagonists from 2003 to 2008, some of which entered clinical trial for multiple sclerosis and other inflammatory conditions, and others show potential in cancer treatment.…”

Predictive Dose-Based Estimation of Systemic Exposure Multiples in Mouse and Monkey Relative to Human for Antisense Oligonucleotides With 2′-O-(2-Methoxyethyl) Modifications

“…The last decade has seen a very rapid increase in the number of 2′-MOE ASOs progressing to phase 1, 2, and 3 clinical trials and targeting ever expanding therapeutic areas of interest including, but certainly not limited to, rheumatoid arthritis, 1 , 2 diabetes, 3 cancer, 4 , 5 hypercholestrolemia, 6 , 7 , 8 and multiple sclerosis. 9 A 2′-MOE ASO, mipomersen (Kynamro), was recently approved by the US FDA as an adjunct to lipid-lowering medications and diet to reduce atherogenic lipids in patients with homozygous familial hypercholesterolemia (HoFH).…”