Amidines as amide bond replacements in VLA-4 antagonists.
Kamenecka TM, Park YJ, Lin LS, de Laszlo S, McCauley ED, Van Riper G, Egger L, Kidambi U, Mumford RA, Tong S, Tang W, Colletti A, Teffera Y, Stearns R, MacCoss M, Schmidt JA, Hagmann WK.
VLA-4 (alpha(4)beta(1), very late activating antigen-4), a key cell surface integrin plays an important role in inflammation by promoting leukocyte attachment and extravasation from the vasculature into the peripheral tissues. As such, VLA-4 antagonists may be useful in the treatment, prevention, and suppression of diseases where cell adhesion and migration are important such as asthma, rheumatoid arthritis, and multiple sclerosis. Herein, we report on the discovery, synthesis, and biological evaluation of amidines as small molecule antagonists of VLA-4.