Neladenoson Bialanate Hydrochloride: A Prodrug of a Partial Adenosine†A1 Receptor Agonist for the Chronic Treatment of Heart Diseases.

Adenosine is known to be released under a variety of physiological and pathophysiological conditions to facilitate the protection and regeneration of injured ischemic tissues. The activation of myocardial adenosine A1 receptors (A1 Rs) has been shown to inhibit myocardial pathologies associated with ischemia and reperfusion injury, suggesting several options for new cardiovascular therapies. When full A1 R agonists are used, the desired protective and regenerative cardiovascular effects are usually overshadowed by unintended pharmacological effects such as induction of bradycardia, atrioventricular (AV) blocks, and sedation. These unwanted effects can be overcome by using partial A1 R agonists. Starting from previously reported capadenoson we evaluated options to tailor A1 R agonists to a specific partiality range, thereby optimizing the therapeutic window. This led to the identification of the potent and selective agonist neladenoson, which shows the desired partial response on the A1 R, resulting in cardioprotection without sedative effects or cardiac AV blocks. To circumvent solubility and formulation issues for neladenoson, a prodrug approach was pursued. The dipeptide ester neladenoson bialanate hydrochloride showed significantly improved solubility and exposure after oral administration. Neladenoson bialanate hydrochloride is currently being evaluated in clinical trials for the treatment of heart failure.

Novel TIE-2 inhibitor BAY-826 displays in vivo efficacy in experimental syngeneic murine glioma models.

Targeting the vascular endothelial growth factor signaling axis in glioblastoma inevitably leads to tumor recurrence and a more aggressive phenotype. Therefore, other angiogenic pathways, like the angiopoietin/tunica interna endothelial cell kinase (TIE) signaling axis, have become additional targets for therapeutic intervention. Here, we explored whether targeting the receptor tyrosine kinase TIE-2 using a novel, highly potent, orally available small molecule TIE-2 inhibitor (BAY-826) improves tumor control in syngeneic mouse glioma models. BAY-826 inhibits TIE-2 phosphorylation in vitro and in vivo as demonstrated by suppression of Angiopoietin-1- or Na3 VO4 -induced TIE-2 phosphorylation in glioma cells or extracts of lungs from BAY-826-treated mice. There was a trend toward prolonged survival upon single-agent treatment in two of four models (SMA-497 and SMA-540) and there was a significant survival benefit in one model (SMA-560). Co-treatment with BAY-826 and irradiation was ineffective in one model (SMA-497), but provided synergistic prolongation of survival in another (SMA-560). Decreased vessel densities and increased leukocyte infiltration were observed, but might be independent processes as the effect was also observed in single treatment modalities. These data demonstrate that TIE-2 inhibition may improve tumor response to treatment in highly vascularized tumors such as glioblastoma.