Chiral Amines in Drug Discovery
Chiral amines are among the most frequently encountered motifs in small-molecule therapeutics. Amines themselves appear in around 40% of the top 200 small-molecule drugs by 2023 sales. The basic nitrogen often mediates key ionic or hydrogen-bonding contacts with a target, while the adjacent stereocentre fixes the three-dimensional orientation of the substituents around it. They appear across a wide range of therapeutic areas, from metabolic drugs such as sitagliptin, built around an \(R\)-β-amino amide, to CNS agents including sertraline. Levocetirizine illustrates how much a single stereocentre can matter. The antihistamine cetirizine is a racemate, with its stereocentre on the benzhydryl carbon directly attached to the piperazine nitrogen. Binding studies at the human H1 receptor reported a Ki of 3 nM for the \(R\)-enantiomer, levocetirizine, compared with 100 nM for \(S\)-cetirizine, a roughly thirty-fold difference. Developing the single enantiomer allowed levocetirizine to be given at half the dose of the racemate, 5 mg rather than 10 mg. The story goes beyond affinity alone. The same study found that levocetirizine dissociated from the H1 receptor with a half-time of 142 minutes, compared with just 6 minutes for \(S\)-cetirizine. This difference in residence time points to pharmacology that is not fully captured by a single binding constant. For medicinal chemists, it is a useful reminder that each enantiomer of a chiral amine may carry its own distinct profile. Access to both, in high enantiopurity and early in a programme, can make those differences visible sooner. Explore our range of building blocks using the advanced search tools at https://lnkd.in/eVbfw6Ua To read more take a look at the following papers 1. Modular synthesis of bis-α-chiral amines using Ellman sulfinamide for consecutive S-to-C chirality induction/transfer https://lnkd.in/eZ\_yz85S 2. The significance of chirality in contemporary drug discovery: a mini review https://lnkd.in/eNHGXKWW 3. Binding characteristics of cetirizine and levocetirizine to human H1 histamine receptors: contribution of Lys191 and Thr194 https://lnkd.in/eJcp\_RKT