Novel tricyclic benzothiazolo[2,3-c]thiadiazine antagonists of the platelet ADP receptor (P2Y(12)).

Novel non-nucleoside tricyclic platelet ADP receptor (P2Y(12)) antagonists have been discovered that bind reversibly and with high affinity to the platelet receptor. Condensation of various 2-aminobenzothiazoles with chlorosulfonylacetyl chloride affords these novel tricyclic heterocycles, which are novel and unpredicted products of this reaction.

The role of alpha and beta platelet-derived growth factor receptor in the vascular response to injury in nonhuman primates.

Restenosis remains a significant clinical problem associated with mechanical interventional procedures for arterial revascularization or repair, including coronary angioplasty and stenting. Studies with rodents have established that platelet-derived growth factor (PDGF), a potent chemotactic and mitogenic agent for vascular smooth muscle cells, is a key mediator of lesion formation after vascular injury. To further explore this hypothesis in a more clinically relevant model, neutralizing monoclonal antibodies (mAbs) were used to examine the effect of selective inhibition of alpha or beta PDGF receptor (PDGFR) on neointima formation in nonhuman primates.

Functional importance of platelet-derived growth factor (PDGF) receptor extracellular immunoglobulin-like domains. Identification of PDGF binding site and neutralizing monoclonal antibodies.

The biological effects of platelet-derived growth factor (PDGF) are mediated by alpha- and beta-PDGF receptors (PDGFR), which have an intracellular tyrosine kinase domain and an extracellular region comprising five immunoglobulin-like domains (D1-D5). Using deletion mutagenesis we mapped the PDGF binding site in each PDGFR to the D2-D3 region. In the case of alpha-PDGFR, 125I-PDGF AA and 125I-PDGF BB bound to the full-length extracellular domain, D1-D5, and D2-D3 with equal affinity (Kd = 0.

Isolation and structure elucidation of five new asterriquinones from Aspergillus, Humicola and Botryotrichum species.

Five new quinone pigments have been discovered from the fermentation broth of Aspergillus, Humicola and Botryotrichum species isolated from different soil samples. These compounds inhibit serine proteases of the coagulation pathway. Their structures which differ in the identity and position of a 5-carbon side chain on the indole moiety have been elucidated based on NMR and FAB-MS experiments.

Mechanism of platelet-derived growth factor (PDGF) AA, AB, and BB binding to alpha and beta PDGF receptor.

The biological effects of platelet-derived growth factor (PDGF) are mediated by cell surface alpha and beta PDGF receptors, which, as a result of ligand binding, undergo dimerization in a manner consistent with PDGF being bivalent. In order to directly demonstrate PDGF bivalency and to define the binding of PDGF AB to isolated beta receptor, we developed solid-phase binding assays using purified recombinant extracellular domain of human PDGF receptors. PDGF AA, AB, and BB were prepared from the monomeric chains expressed in Escherichia coli, and each was purified to homogeneity; PDGF AB contained < 0.