Highly constrained bicyclic VLA-4 antagonists

…, M MacCoss, K Lyons, E McCauley, R Mumford…

Index: Chang, Linda L.; Truong, Quang; Doss, George A.; MacCoss, Malcolm; Lyons, Kathryn; McCauley, Ermengilda; Mumford, Richard; Forrest, Gail; Vincent, Stella; Schmidt, John A.; Hagmann, William K. Bioorganic and Medicinal Chemistry Letters, 2007 , vol. 17, # 3 p. 597 - 601

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Citation Number: 18

Abstract

VLA-4 is implicated in several inflammatory and autoimmune disease states. A series of cyclic β-amino acids (β-aa) was studied as VLA-4 antagonists. Binding affinity was highly dependent on the dihedral angle (ϕ) between the amino and the carboxyl termini of the β- aa. Compound 5m where the β-aa is embedded in a bicycle possesses the most preferred ϕ (120°). It is a potent and bioavailable VLA-4 antagonist (VCAM-Ig α4β1 IC50= 54nM, rat ...