A new method able to measure the concentration of oxygen in complex biological systems, including in vivo, has been developed using low-frequency EPR and newly characterized free radicals that are very sensitive to the concentration of oxygen. The free radicals (fusinite and lithium phthalocyanine) are very stable in tissues (for at least 150 days), apparently nontoxic, and can reflect oxygen concentrations that are less than the Km of cytochrome oxidase (0.1 microM or lower). Their biological stability is indicated by the fact that repeated measurements with fusinite of the concentration of oxygen in skeletal muscle have been made in the same animal for more than 150 days without any change in sensitivity or signs of toxicity.

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Sodium-hydrogen exchanger isoform 1 (NHE1) is a ubiquitously expressed transmembrane ion channel responsible for intracellular pH regulation. During myocardial ischemia, low pH activates NHE1 and causes increased intracellular calcium levels and aberrant cellular processes, leading to myocardial stunning, arrhythmias, and ultimately cell damage and death. The role of NHE1 in cardiac injury has prompted interest in the development of NHE1 inhibitors for the treatment of heart failure. This report outlines our efforts to identify a compound suitable for once daily, oral administration with low drug-drug interaction potential starting from NHE1 inhibitor sabiporide. Substitution of a piperidine for the piperazine of sabiporide followed by replacement of the pyrrole moiety and subsequent optimization to improve potency and eliminate off-target activities resulted in the identification of N-[4-(1-acetyl-piperidin-4-yl)-3-trifluoromethyl-benzoyl]-guanidine (60). Pharmacological evaluation of 60 revealed a remarkable ability to prevent ischemic damage in an ex vivo model of ischemia reperfusion injury in isolated rat hearts.

The Kinase insert Domain containing Receptor (KDR), alternatively referred to as VEGFR-2, is a receptor for Vascular Endothelial Growth Factors (VEGFs) and functions as a key regulator of angiogenesis, the process by which new capillaries are created from preexisting blood vessels. The induction of angiogenesis, or the "angiogenic switch," is a critical step in tumor progression, and inhibitors of KDR have been demonstrated both to induce tumor regression and reduce metastatic potential in preclinical models. In the last few years, medicinal chemists have expanded the kinase selectivity profile of known inhibitor classes to include KDR, and also identified novel classes of KDR inhibitors. This review presents structure activity relationships (SAR) of small molecule inhibitors of KDR, with an emphasis on the pharmacophore elements of the scaffolds employed. Binding hypotheses based on X-ray crystallographic analyses will also be described. Additionally, the efficacy of representative compounds in in vitro and in vivo models of tumor progression and angiogenesis are discussed.