Click 1,2,3-triazoles in drug discovery and development: From the flask to the clinic?

After 20 years since its conception, click chemistry has come of age and we believe the time has come to evaluate if the copper-catalyzed azide alkyne cycloaddition (CuCAAC) reaction deserves to be considered the perfect transformation in medicinal chemistry campaigns and to weigh up the concrete results that have been produced in terms of drugs approved and clinical candidates in development. After a description of the properties of the triazole nucleus in terms of both pharmacokinetic and pharmacodynamic profile, a practical guide for the best approaches to be used for the synthesis of triazoles is provided, capitalizing on our 20-year hands-on experience in this chemistry. Finally, we describe those molecules displaying the 1,2,3-triazole nucleus that have entered the market or are, at least, in clinical trials. Only four 1,2,3-triazole-bearing drugs have been launched so far. Among them the recently approved antibody drug conjugate sacituzumab govitecan was discovered thanks to click chemistry. Nevertheless, to the best of our knowledge, there are a dozen 1,2,3-triazoles in clinical development and it is likely that we will witness the launch on the market of at least some of them, encouraging medicinal chemists to further use this approach, not only as a route to early-stage discoveries, but also as a means to developing successful drugs.