1-(3-tert-Butyl-4-hy­droxy­phen­yl)ethanone

The title compound, C12H16O2, is approximately planar (r.m.s. deviation = 0.030 Å), apart from two methyl groups of the tert-butyl unit [deviations of the C atoms = 1.140 (2) and −1.367 (1) Å]. In the crystal, inter­molecular O—H⋯O hydrogen bonds link the mol­ecules into hexa­meric rings with R 6 6(48) graph-set motifs

Discovery of 1,3-Diaminobenzenes as Selective Inhibitors of Platelet Activation at the PAR1 Receptor

A high-throughput screen of the NIH-MLSMR compound collection, along with a series of secondary assays to identify potential targets of hit compounds, previously identified a 1,3-diaminobenzene scaffold that targets protease-activated receptor 1 (PAR1). We now report additional structure–activity relationship (SAR) studies that delineate the requirements for activity at PAR1 and identify plasma-stable analogues with nanomolar inhibition of PAR1-mediated platelet activation. Compound 4 was declared as a probe (ML161) with the NIH Molecular Libraries Program. This compound inhibited platelet aggregation induced by a PAR1 peptide agonist or by thrombin but not by several other platelet agonists. Initial studies suggest that ML161 is an allosteric inhibitor of PAR1. These findings may be important for the discovery of antithrombotics with an improved safety profile

Parmodulins Inhibit Thrombus Formation Without Inducing Endothelial Injury Caused by Vorapaxar

Protease-activated receptor-1 (PAR1) couples the coagulation cascade to platelet activation during myocardial infarction and to endothelial inflammation during sepsis. This receptor demonstrates marked signaling bias. Its activation by thrombin stimulates prothrombotic and proinflammatory signaling, whereas its activation by activated protein C (APC) stimulates cytoprotective and antiinflammatory signaling. A challenge in developing PAR1-targeted therapies is to inhibit detrimental signaling while sparing beneficial pathways. We now characterize a novel class of structurally unrelated small-molecule PAR1 antagonists, termed parmodulins, and compare the activity of these compounds to previously characterized compounds that act at the PAR1 ligand–binding site. We find that parmodulins target the cytoplasmic face of PAR1 without modifying the ligand-binding site, blocking signaling through Gαq but not Gα13 in vitro and thrombus formation in vivo. In endothelium, parmodulins inhibit prothrombotic and proinflammatory signaling without blocking APC-mediated pathways or inducing endothelial injury. In contrast, orthosteric PAR1 antagonists such as vorapaxar inhibit all signaling downstream of PAR1. Furthermore, exposure of endothelial cells to nanomolar concentrations of vorapaxar induces endothelial cell barrier dysfunction and apoptosis. These studies demonstrate how functionally selective antagonism can be achieved by targeting the cytoplasmic face of a G-protein–coupled receptor to selectively block pathologic signaling while preserving cytoprotective pathways

Platelet thrombin receptor antagonism and atherothrombosis

Clinical manifestations of atherothrombotic disease, such as acute coronary syndromes, cerebrovascular events, and peripheral arterial disease, are major causes of mortality and morbidity worldwide. Platelet activation and aggregation are ultimately responsible for the progression and clinical presentations of atherothrombotic disease. The current standard of care, dual oral antiplatelet therapy with aspirin and the P2Y12 adenosine diphosphate (ADP) receptor inhibitor clopidogrel, has been shown to improve outcomes in patients with atherothrombotic disease. However, aspirin and P2Y12 inhibitors target the thromboxane A2 and the ADP P2Y12 platelet activation pathways and minimally affect other pathways, while agonists such as thrombin, considered to be the most potent platelet activator, continue to stimulate platelet activation and thrombosis. This may help explain why patients continue to experience recurrent ischaemic events despite receiving such therapy. Furthermore, aspirin and P2Y12 receptor antagonists are associated with bleeding risk, as the pathways they inhibit are critical for haemostasis. The challenge remains to develop therapies that more effectively inhibit platelet activation without increasing bleeding complications. The inhibition of the protease-activated receptor-1 (PAR-1) for thrombin has been shown to inhibit thrombin-mediated platelet activation without increasing bleeding in pre-clinical models and small-scale clinical trials. PAR-1 inhibition in fact does not interfere with thrombin-dependent fibrin generation and coagulation, which are essential for haemostasis. Thus PAR-1 antagonism coupled with existing dual oral antiplatelet therapy may potentially offer more comprehensive platelet inhibition without the liability of increased bleeding

Cytotoxic Terpene Quinones from Marine Sponges

The 1,4-benzoquinone moiety is a common structural feature in a large number of compounds that have received considerable attention owing to their broad spectrum of biological activities. The cytotoxic and antiproliferative properties of many natural sesquiterpene quinones and hydroquinones from sponges of the order Dictyoceratida, such as avarol, avarone, illimaquinone, nakijiquinone and bolinaquinone, offer promising opportunities for the development of new antitumor agents. The present review summarizes the structure and cytotoxicity of natural terpenequinones/hydroquinones and their bioactive analogues and derivatives