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Small Macrocycles As Highly Active Integrin ?2?1 Antagonists.

ABSTRACT: Starting from clinical candidates Firategrast, Valategrast, and AJM-300, a series of novel macrocyclic platelet collagen receptor ?2?1 antagonists were developed. The amino acid derived low molecular weight 14-18-membered macrocycles turned out to be highly active toward integrin ?2?1 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 ?1 unit revealed a binding model indicating key binding features. Macrocycle 38 was selected for further in vitro and in vivo profiling.

SUBMITTER: Halland N

PROVIDER: S-EPMC4027761 | biostudies-literature | 2014 Feb

REPOSITORIES: biostudies-literature

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Small Macrocycles As Highly Active Integrin α2β1 Antagonists.

Halland Nis N Blum Horst H Buning Christian C Kohlmann Markus M Lindenschmidt Andreas A

ACS medicinal chemistry letters 20140110 2

Starting from clinical candidates Firategrast, Valategrast, and AJM-300, a series of novel macrocyclic platelet collagen receptor α2β1 antagonists were developed. The amino acid derived low molecular weight 14-18-membered macrocycles turned out to be highly active toward integrin α2β1 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 ...[more]

PMID: 24900800

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