Phosphinanes and Azaphosphinanes as Potent and Selective Inhibitors of Activated Thrombin-Activatable Fibrinolysis Inhibitor (TAFIa)

Abstract

Selective and potent inhibitors of activated thrombin activatable fibrinolysis inhibitor (TAFIa) have the potential to increase endogenous and therapeutic fibrinolysis and to behave like profibrinolytic agents without the risk of major hemorrhage, since they do not interfere either with platelet activation or with coagulation during blood hemostasis. Therefore, TAFIa inhibitors could be used in at-risk patients for the treatment, prevention, and secondary prevention of stroke, venous thrombosis, and pulmonary embolisms. In this paper, we describe the design, the structure–activity relationship (SAR), and the synthesis of novel, potent, and selective phosphinanes and azaphosphinanes as TAFIa inhibitors. Several highly active azaphosphinanes display attractive properties suitable for further in vivo efficacy studies in thrombosis models.

Accessing Five- and Seven-Membered Phosphorus-Based Heterocycles via Cycloaddition Reactions of Azophosphines

“…[9][10][11] There are fewer examples of P/N heterocycles that contain solely P-C bonds, but heteroocycles fo this type recently have been applied as ligands for Ni in electrocatalysts or as chelating ligands for lanthanide ions, [12][13][14] and in medicinal applications (Figure 1A). 15 Azaphosphepines are unsaturated seven-membered P/N heterocycles, and convenient and high-yielding synthetic routes to such heterocycles remain limited in scope. The most pertinent examples of azaphosphepine synthesis for this current study are ring-expansions via P-N cleavage of an appropriate five-membered ring precursor.…”

Late-Stage N-Me Selective Arylation of Trialkylamines Enabled by Ni/Photoredox Dual Catalysis

“…If accomplished, it would offer new opportunities to rapidly access novel benzyl dialkylaminesprivileged moieties embedded within many bioactive molecules and lead compoundswith complementarity to classical alkylation or reductive amination strategies from secondary amines, where the complex benzaldehydes or benzyl electrophiles are often difficult to access …”