title: Small Macrocycles As Highly Active Integrin α2β1 Antagonists.
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.
authors.affiliation: Sanofi R&D , Industriepark Höchst Building G838, D-65926 Frankfurt am Main, Germany.
authors.forename: Nis
authors.initials: N
authors.lastname: Halland
authors.affiliation: Sanofi R&D , Industriepark Höchst Building G838, D-65926 Frankfurt am Main, Germany.
authors.forename: Horst
authors.initials: H
authors.lastname: Blum
authors.affiliation: Sanofi R&D , Industriepark Höchst Building G838, D-65926 Frankfurt am Main, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Buning
authors.affiliation: Sanofi R&D , Industriepark Höchst Building G838, D-65926 Frankfurt am Main, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Kohlmann
authors.affiliation: Sanofi R&D , Industriepark Höchst Building G838, D-65926 Frankfurt am Main, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Lindenschmidt
keywords: Integrin; macrocycle; metathesis; platelet collagen receptor; restricted conformation