Stereochemical comparison of nebivolol with other β‐blockers

Abstract

beta-Blockers are widely used in the treatment of cardiovascular disease and act by antagonizing the effects of adrenaline (epinephrine) and noradrenaline (norepinephrine) on beta-adrenergic receptors. All beta-blockers currently used in the treatment of cardiovascular disease contain at least one chiral center and, while most are marketed as racemates, their cardiac antihypertensive activity generally resides in the S-enantiomer. Nebivolol is a third generation beta-blocker that is highly selective for the beta(1)-adrenoceptor. The nebivolol molecule contains four chiral centers and is marketed as a racemate of (+)-nebivolol (SRRR-configuration) and (-)-nebivolol (RSSS-configuration). Nebivolol differs from all other beta-blockers with a hydroxypropanolamine substructure in that its cardiac antihypertensive activity resides in the R-enantiomer at the hydroxy group, whereas all other beta-blockers have antihypertensive activity in the S-enantiomer. Two of the four chiral centers in nebivolol are part of a ring structure and the increased rigidity of this structure may be related to nebivolol's divergence from the standard pharmacophore model of beta-blockers.

Different Pharmacological Properties of Two Enantiomers in a Unique β‐Blocker, Nebivolol

“…Contrary to all other β‐blockers, nebivolol displays an evident symmetrical configuration, with a complex structure developing from a central nitrogen atom (Janssen 1991; Siebert et al 2007). A common feature of conventional β‐blockers is an aromatic or heteroaromatic ring structure (commonly OCH 2 CH(OH)CH 2 NHR, where R varies among β‐blockers) attached to the oxypropanolamine structure through the oxygen atom via an ether bridge.…”

“…A common feature of conventional β‐blockers is an aromatic or heteroaromatic ring structure (commonly OCH 2 CH(OH)CH 2 NHR, where R varies among β‐blockers) attached to the oxypropanolamine structure through the oxygen atom via an ether bridge. However, nebivolol has a distinct structure in which the oxygen atom is incorporated into a fluorochroman structure that directly connects to the central bis‐iminodiethanol structure (Labrid et al 1989; Siebert et al 2007).…”

Lipid Simulations: A Perspective on Lipids in Action

“…Meanwhile, nebivolol is a new, highly selective b1-AR blocker (Prisant et al 2008) characterized by lack of side effects that are otherwise typical for b-blockers, and also lack of interactions with other drugs (Veverka et al 2006). Nebivolol has four chiral centers and 10 stereoisomers, though only two of them are of pharmaceutical interest: the srrr-form and the rsss-form (Siebert et al 2008).…”

Nebivolol, but Not Metoprolol, Improves Endothelial Function of the Corpus Cavernosum in Apolipoprotein E-Knockout Mice

“…Decrease of fibrotic changes is also probably related to a decrease of oxidative stress. ␤-blockers currently used have at least one chiral center, and beneficial cardiovascular effects may reside in the S-enantiomer (Siebert et al, 2008). Nebivolol is a racemic mixture and differs from all ␤-blockers with a hydroxypropanolamine structure with cardiovascular activity at the Renantiomer at the hydroxy group.…”

“…Nebivolol is a racemic mixture and differs from all ␤-blockers with a hydroxypropanolamine structure with cardiovascular activity at the Renantiomer at the hydroxy group. Moreover, hydroxylated nebivolol metabolites could play a role in beneficial effects beyond blood pressure reduction (Siebert et al, 2008). Recent results in rat aorta suggested that nebivolol is in part degraded by its reaction with ROS (de Groot et al, 2004).…”