Current Topics in Medicinal Chemistry - Volume 4, Issue 14, 2004

A number of studies appearing in the mid-1990s employing antibody reagents and gene ablation technologies offered promise for a role of VLA-4 in a number of inflammatory diseases including asthma, rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, type I diabetes and atherosclosis. A brief summary and leading references are provided in reference [1]. These findings prompted a number of firms, amon Read More

Through a directed screening of a combinatorial library containing carboxylic acids, N-sulfonylated dipeptides were identified as leads in the Merck Research Laboratories VLA-4 antagonist program. Further optimization quickly identified subnanomolar compounds with varying degrees of specificity over the related integrin α4β7. Various metabolic liabilities were identified and addressed. However, the pharmacokinetic pro Read More

The identification of orally active, small molecule antagonists of the α4β1 integrin, VLA-4, could lead to therapeutic agents with utility in a number of clinical settings, including asthma, multiple sclerosis and IBD. Starting from CDR3 sequences conserved among neutralizing α4 antibodies, peptides were identified that antagonized VLA-4 mediated adhesion in vitro. Through a series of structural modifications, these peptides Read More

The β2 integrins are validated therapeutic targets for inflammatory disorders. Two distinct mechanistic classes of small molecule inhibitors, termed α I allosteric and α / β I-like allosteric antagonist, have recently been developed. The α I allosteric antagonists bind underneath the C-terminal helix of the I domain and stabilize the I domain in the inactive closed conformation. By contrast, the α / β I-like allosteric antagonists bind to th Read More

Asthma, a chronic inflammatory disease of the airways, is a significant burden on our healthcare system. There is high unmet need for treatments directed towards the underlying causes of the disease. The cell surface integrin VLA-4 (very late antigen-4; α4β1; CD49d / CD29) plays an important role in the trafficking of white blood cells to sites of inflammation and represents an exciting target for the development of novel anti-infl Read More

Starting with a cyclic peptide of moderate potency as a VLA-4 antagonist, highly potent and conformationally defined cyclic peptides were developed incorporating a constrained tyrosine and an achiral Asp-Pro spacer. N-Acyl phenylalanine derivatives were also discovered to have VLA-4 antagonist activity. During the course of development of this series, we found that the active acylphenylalanines mimic the pharmacoph Read More