Peter Fey

Discovery of the Soluble Guanylate Cyclase Stimulator Vericiguat (BAY 1021189) for the Treatment of Chronic Heart Failure

The first-in-class soluble guanylate cyclase (sGC) stimulator riociguat was recently introduced as a novel treatment option for pulmonary hypertension. Despite its outstanding pharmacological profile, application of riociguat in other cardiovascular indications is limited by its short half-life, necessitating a three times daily dosing regimen. In our efforts to further optimize the compound class, we have uncovered interesting structure-activity relationships and were able to decrease oxidative metabolism significantly. These studies resulting in the discovery of once daily sGC stimulator vericiguat (compound 24, BAY 1021189), currently in phase 3 trials for chronic heart failure, are now reported.

Regio- and stereoselective a4-umpolung reactions of α,β-unsaturated esters to 1,6-dicarbonyl compounds by addition of enantiopure nucleophiles to racemic tetracarbonyl (η3-alyl)iron(1+) complexes

Abstract The nucleophilic addition of various enantiopure d2-carbon nucleophiles (chiral enamines 1 or metalated imines 2 and silylketon derivatives 3) to racemic planar chiral electrophilic tetracarbonyl(η3-allyl)iron(1+) complexes 5 proceeds with complete γ-radioselectivity and with kinetic resolution of complex 5. Subsequent oxidative demetalation provides access to enantiometrically enriched (ee 92%) 1,6-dicarbonyl compounds 7 in moderate overall yields (14–53%, four steps or 5–21%, five steps) and with retention of The (E-double bond geometry with respect to the starting material 4.