13 research outputs found
Small Macrocycles As Highly Active Integrin Ī±2Ī²1 Antagonists
Starting from clinical candidates
Firategrast, Valategrast, and
AJM-300, a series of novel macrocyclic platelet collagen receptor
Ī±2Ī²1 antagonists were developed. The amino acid derived
low molecular weight 14ā18-membered macrocycles turned out
to be highly active toward integrin Ī±2Ī²1 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 Ī²1 unit revealed
a binding model indicating key binding features. Macrocycle <b>38</b> was selected for further in vitro and in vivo profiling
Mass Spectrometric Analysis of Noncovalent Complexes Between Synthetic Peptides from Human Ribosomal Protein L7 and Protein G
<div><p>In order to gain a comprehensive insight into the complexes of human ribosomal protein L7 with protein G in a certain degree, an investigation on the complexes of five synthetic L7 peptides, containing the basic-region-leucine-zipper (BZIP)-like domain (aa 15ā49), with protein G was performed using nanoelectrospray ionization mass spectrometry (nanoESI-MS). Circular dichroism (CD) was used to characterize the secondary structures of L7 peptides. The characteristics of the complexes between L7 peptides and protein G were studied under various conditions, such as molar ratio of ligands, solvent condition, declustering potential, and peptide sequence. The stability of the complexes is found to decrease with increased declustering potential (>20Ā V), decreased pH (<5), increased pH (>5), while L7 peptide sequence had no obvious effect on the complex formation. Taken together, the complexes of L7 peptides with protein G are specific noncovalent binding with 1:1 stoichiometry. Because of the availability of synthetic L7 peptides, they might be used as baits to discover the binding partners of protein L7. Furthermore, the elaboration of the binding mechanisms of L7 peptides with protein G could benefit further application of protein G.</p></div
Sulfamide as Zinc Binding Motif in Small Molecule Inhibitors of Activated Thrombin Activatable Fibrinolysis Inhibitor (TAFIa)
Previously disclosed
TAFIa inhibitors having a urea zinc-binding
motif were used as the starting point for the development of a novel
class of highly potent inhibitors having a sulfamide zinc-binding
motif. High-resolution X-ray cocrystal structures were used to optimize
the structures and reveal a highly unusual sulfamide configuration.
A selected sulfamide was profiled in vitro and in vivo and displayed
a promising ADMET profile
Sulfamide as Zinc Binding Motif in Small Molecule Inhibitors of Activated Thrombin Activatable Fibrinolysis Inhibitor (TAFIa)
Previously disclosed
TAFIa inhibitors having a urea zinc-binding
motif were used as the starting point for the development of a novel
class of highly potent inhibitors having a sulfamide zinc-binding
motif. High-resolution X-ray cocrystal structures were used to optimize
the structures and reveal a highly unusual sulfamide configuration.
A selected sulfamide was profiled in vitro and in vivo and displayed
a promising ADMET profile
Sulfamide as Zinc Binding Motif in Small Molecule Inhibitors of Activated Thrombin Activatable Fibrinolysis Inhibitor (TAFIa)
Previously disclosed
TAFIa inhibitors having a urea zinc-binding
motif were used as the starting point for the development of a novel
class of highly potent inhibitors having a sulfamide zinc-binding
motif. High-resolution X-ray cocrystal structures were used to optimize
the structures and reveal a highly unusual sulfamide configuration.
A selected sulfamide was profiled in vitro and in vivo and displayed
a promising ADMET profile
Novel Small Molecule Inhibitors of Activated Thrombin Activatable Fibrinolysis Inhibitor (TAFIa) from Natural Product Anabaenopeptin
Anabaenopeptins isolated from cyanobacteria
were identified as
inhibitors of carboxypeptidase TAFIa. Cocrystal structures of these
macrocyclic natural product inhibitors in a modified porcine carboxypeptidase
B revealed their binding mode and provided the basis for the rational
design of small molecule inhibitors with a previously unknown central
urea motif. Optimization based on these design concepts allowed for
a rapid evaluation of the SAR and delivered potent small molecule
inhibitors of TAFIa with a promising overall profile
Identification of High-Affinity P2Y<sub>12</sub> Antagonists Based on a Phenylpyrazole Glutamic Acid Piperazine Backbone
A series of novel, highly potent P2Y<sub>12</sub> antagonists
as
inhibitors of platelet aggregation based on a phenylpyrazole glutamic
acid piperazine backbone is described. Exploration of the structural
requirements of the substituents by probing the structureāactivity
relationship along this backbone led to the discovery of the <i>N</i>-acetyl-(<i>S</i>)-proline cyclobutyl amide moiety
as a highly privileged motif. Combining the most favorable substituents
led to remarkably potent P2Y<sub>12</sub> antagonists displaying not
only low nanomolar binding affinity to the P2Y<sub>12</sub> receptor
but also a low nanomolar inhibition of platelet aggregation in the
human platelet rich plasma assay with IC<sub>50</sub> values below
50 nM. Using a homology and a three-dimensional quantitative structureāactivity
relationship model, a binding hypothesis elucidating the impact of
several structural features was developed
Novel Ī²āAmino 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 Ī²-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
Image5_An orally available small molecule that targets soluble TNF to deliver anti-TNF biologic-like efficacy in rheumatoid arthritis.tif
Tumor necrosis factor (TNF) is a pleiotropic cytokine belonging to a family of trimeric proteins with both proinflammatory and immunoregulatory functions. TNF is a key mediator in autoimmune diseases and during the last couple of decades several biologic drugs have delivered new therapeutic options for patients suffering from chronic autoimmune diseases such as rheumatoid arthritis and chronic inflammatory bowel disease. Attempts to design small molecule therapies directed to this cytokine have not led to approved products yet. Here we report the discovery and development of a potent small molecule inhibitor of TNF that was recently moved into phase 1 clinical trials. The molecule, SAR441566, stabilizes an asymmetrical form of the soluble TNF trimer, compromises downstream signaling and inhibits the functions of TNF in vitro and in vivo. With SAR441566 being studied in healthy volunteers we hope to deliver a more convenient orally bioavailable and effective treatment option for patients suffering with chronic autoimmune diseases compared to established biologic drugs targeting TNF.</p
Image4_An orally available small molecule that targets soluble TNF to deliver anti-TNF biologic-like efficacy in rheumatoid arthritis.tif
Tumor necrosis factor (TNF) is a pleiotropic cytokine belonging to a family of trimeric proteins with both proinflammatory and immunoregulatory functions. TNF is a key mediator in autoimmune diseases and during the last couple of decades several biologic drugs have delivered new therapeutic options for patients suffering from chronic autoimmune diseases such as rheumatoid arthritis and chronic inflammatory bowel disease. Attempts to design small molecule therapies directed to this cytokine have not led to approved products yet. Here we report the discovery and development of a potent small molecule inhibitor of TNF that was recently moved into phase 1 clinical trials. The molecule, SAR441566, stabilizes an asymmetrical form of the soluble TNF trimer, compromises downstream signaling and inhibits the functions of TNF in vitro and in vivo. With SAR441566 being studied in healthy volunteers we hope to deliver a more convenient orally bioavailable and effective treatment option for patients suffering with chronic autoimmune diseases compared to established biologic drugs targeting TNF.</p