RESUMEN
Starting from clinical candidates Firategrast, Valategrast, and AJM-300, a series of novel macrocyclic platelet collagen receptor α2ß1 antagonists were developed. The amino acid derived low molecular weight 14-18-membered macrocycles turned out to be highly active toward integrin α2ß1 with IC50s in the low nanomolar range. The conformation of the macrocycles was found to be highly important for the activity, and an X-ray crystal structure was obtained to clarify this. Subsequent docking into the metal-ion-dependent adhesion site (MIDAS) of a ß1 unit revealed a binding model indicating key binding features. Macrocycle 38 was selected for further in vitro and in vivo profiling.
RESUMEN
A versatile and efficient palladium catalyzed domino reaction leading to a broad range of substituted 1-aminoindoles has been developed. The title compounds were prepared from 2-halo-phenylacetylenes and simple hydrazines in good to excellent yields in just a few hours under mild conditions.
