Synthesis of constrained L-phenylalanine derivatives incorporating a benzazepinone or an azepinone ring as VCAM/VLA-4 antagonists

Novel constrained L-phenylalanine derivatives incorporating a benzazepinone or an azepinone ring were synthesized in 13 and 8 steps, respectively, emp loying a key base-catalyzed intramolecular cyclization reaction. The produc t, 2, was comparable in potency in a VCAM/VLA-4 ELISA assay to the correspo nding unconstrained analog I suggesting that cyclization favored the bioact ive conformation. However, compound 4 was 100-fold less potent than the unc onstrained analog 3. (C) 2001 Elsevier Science Ltd. All rights reserved.