Abstract:
: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 metal-ion-dependent adhesion site (MIDAS) of a β1 unit revealed a binding model indicating key binding features. Macrocycle 38 was selected for further in vitro and in vivo profiling.
journal_name
ACS Med Chem Lettjournal_title
ACS medicinal chemistry lettersauthors
Halland N,Blum H,Buning C,Kohlmann M,Lindenschmidt Adoi
10.1021/ml4004556subject
Has Abstractpub_date
2014-01-10 00:00:00pages
193-8issue
2issn
1948-5875journal_volume
5pub_type
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