Discovery of potent and selective orally bioavailable β-substituted phenylalanine derived dipeptidyl peptidase IV inhibitors

anti-Substituted biaryl β-methylphenylalanine derived amides have been shown to be potent DPP-IV inhibitors that suffer from suboptimal selectivity and pharmacokinetics. This letter describes the substitution of the β-methyl substituent with β-polar substituents, culminating in the discovery of a β-dimethylamide substituted phenylalanine derivative with an excellent potency, selectivity, and pharmacokinetic profile.

Graphical abstractanti-Substituted biaryl β-methylphenylalanine derived amides have been shown to be potent DPP-IV inhibitors that suffer from suboptimal selectivity and pharmacokinetics. This letter describes the substitution of the β-methyl substituent with β-polar substituents, culminating in the discovery of a β-dimethylamide substituted phenylalanine derivative with an excellent potency, selectivity, and pharmacokinetic profile.Figure optionsDownload full-size imageDownload as PowerPoint slide