12 research outputs found
Small Macrocycles As Highly Active Integrin α2β1 Antagonists
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 IC<sub>50</sub>s 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 <b>38</b> was selected for further in vitro and in vivo profiling
Novel β‑Amino Acid Derivatives as Inhibitors of Cathepsin A
Cathepsin A (CatA) is a serine carboxypeptidase distributed
between
lysosomes, cell membrane, and extracellular space. Several peptide
hormones including bradykinin and angiotensin I have been described
as substrates. Therefore, the inhibition of CatA has the potential
for beneficial effects in cardiovascular diseases. Pharmacological
inhibition of CatA by the natural product ebelactone B increased renal
bradykinin levels and prevented the development of salt-induced hypertension.
However, so far no small molecule inhibitors of CatA with oral bioavailability
have been described to allow further pharmacological profiling. In
our work we identified novel β-amino acid derivatives as inhibitors
of CatA after a HTS analysis based on a project adapted fragment approach.
The new inhibitors showed beneficial ADME and pharmacokinetic profiles,
and their binding modes were established by X-ray crystallography.
Further investigations led to the identification of a hitherto unknown
pathophysiological role of CatA in cardiac hypertrophy. One of our
inhibitors is currently undergoing phase I clinical trials