Highly constrained bicyclic VLA-4 antagonists.

Linda L Chang; Quang Truong; George A Doss; Malcolm MacCoss; Kathryn Lyons; Ermengilda McCauley; Richard Mumford; Gail Forrest; Stella Vincent; John A Schmidt; William K Hagmann

doi:10.1016/j.bmcl.2006.11.011

PubMed · 17118652

Highly constrained bicyclic VLA-4 antagonists.

Linda L Chang·Quang Truong·George A Doss·Malcolm MacCoss·Kathryn Lyons·Ermengilda McCauley·Richard Mumford·Gail Forrest·Stella Vincent·John A Schmidt·William K Hagmann

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Abstract

VLA-4 is implicated in several inflammatory and autoimmune disease states. A series of cyclic beta-amino acids (beta-aa) was studied as VLA-4 antagonists. Binding affinity was highly dependent on the dihedral angle (phi) between the amino and the carboxyl termini of the beta-aa. Compound 5 m where the beta-aa is embedded in a bicycle possesses the most preferred phi (120 degrees). It is a potent and bioavailable VLA-4 antagonist (VCAM-Ig alpha4beta1 IC50 = 54 nM, rat po F = 49%).

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Biological Availability Bridged Bicyclo Compounds Half-Life Humans Indicators and Reagents Integrin alpha4beta1 Integrins Jurkat Cells Magnetic Resonance Spectroscopy Molecular Conformation Stereoisomerism Structure-Activity Relationship Vascular Cell Adhesion Molecule-1 Journal Article

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Linda L Chang, Quang Truong, George A Doss, Malcolm MacCoss, Kathryn Lyons, Ermengilda McCauley, Richard Mumford, Gail Forrest, Stella Vincent, John A Schmidt, William K Hagmann. 2006-11-07. Highly constrained bicyclic VLA-4 antagonists.. https://doi.org/10.1016/j.bmcl.2006.11.011

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