3 research outputs found

    Interview Survey of Chief Executives of Medium-sized Companies Vol.30

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    Additional file 4. Densitometric analysis of troponin T, periostin, carbonic anhydrase 3 and cytoglobin in sham, MI-placebo and MI-SAR1 mice. The densitometric measurements of proteins are expressed as a percentage of the average values measured in the sham group. Results are expressed as mean ± SEM

    Identification of High-Affinity P2Y<sub>12</sub> Antagonists Based on a Phenylpyrazole Glutamic Acid Piperazine Backbone

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    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 structure–activity 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 structure–activity relationship model, a binding hypothesis elucidating the impact of several structural features was developed

    Novel β‑Amino Acid Derivatives as Inhibitors of Cathepsin A

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    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
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