The first formal qualification of safety biomarkers for regulatory decision making marks a milestone in the application of biomarkers to drug development. Following submission of drug toxicity studies and analyses of biomarker performance to the Food and Drug Administration (FDA) and European Medicines Agency (EMEA) by the Predictive Safety Testing Consortium's (PSTC) Nephrotoxicity Working Group, seven renal safety biomarkers have been qualified for limited use in nonclinical and clinical drug development to help guide safety assessments. This was a pilot process, and the experience gained will both facilitate better understanding of how the qualification process will probably evolve and clarify the minimal requirements necessary to evaluate the performance of biomarkers of organ injury within specific contexts.
A small series of compounds is described in which a narrow SAR has identified N,N-dimethyl-3,4-diphenyl-1H-pyrazole-1-propanamine, 3, as a potential antidepressant with reduced side effects. The isomeric N,N-dimethyl-4,5-diphenyl-1H-pyrazole-1-propanamine was completely inactive in the primary antidepressant screens. Compounds were synthesized by Michael addition of acrylonitrile to diphenylpyrazole followed by reductive alkylation of the resultant diphenylpyrazolepropionitriles. Compound 3 was equipotent with imipramine in standard antidepressant assays in animals but showed no significant anticholinergic action and did not antagonize the antihypertensive effects of clonidine and guanethidine.
Drug-induced vascular injury (DIVI) is a nonclinical finding that often confounds the toxicological evaluation of investigational drugs, but there is an absence of qualified biomarkers that can be used to detect and monitor its appearance in animals and patients during drug development and clinical use. It is well known that endothelial cell (EC) activation plays a key role in the expression and evolution of DIVI, and the various immunological and inflammatory factors involved in its expression may serve as potential biomarker candidates. Activated ECs change their morphology and gene expression, generating endothelial adhesion molecules, pro-coagulant molecules, cytokines, chemokines, vasodilators, nitric oxide, and acute-phase reactants. This review provides a brief historical background of EC activation and the search for biomarkers of early EC activation for monitoring DIVI. At present, no biomarkers of EC activation have been qualified to predict DIVI in the nonclinical or clinical context, and a robust pathologic foundation for their use is still lacking. We propose three categories of EC activation biomarkers: recommended surrogate markers, potentially useful markers, and emerging candidate markers. This review alerts pharmaceutical companies, research institutions, and regulatory agencies to the continuing need for reliable biomarkers of EC activation in drug development.
Pulmonary arterial hypertension (PAH) remains a life-limiting condition with a major impact on the ability to lead a normal life. Although existing therapies may improve the outlook in some patients there remains a major unmet need to develop more effective therapies in this condition. There have been significant advances in our understanding of the genetic, cell and molecular basis of PAH over the last few years. This research has identified important new targets that could be explored as potential therapies for PAH. In this review we discuss whether further exploitation of vasoactive agents could bring additional benefits over existing approaches. Approaches to enhance smooth muscle cell apotosis and the potential of receptor tyrosine kinase inhibition are summarised. We evaluate the role of inflammation, epigenetic changes and altered glycolytic metabolism as potential targets for therapy, and whether inherited genetic mutations in PAH have revealed druggable targets. The potential of cell based therapies and gene therapy are also discussed. Potential candidate pathways that could be explored in the context of experimental medicine are identified.
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