Harnessing the necessary nitrogen atom in chemical biology and drug discovery

Despite 80 years of progress in modern small molecule drug discovery, medicinal chemists still struggle to minimize the number and duration of design cycles required to optimize hit and lead compounds into high-quality chemical probes or safe and efficacious clinical candidates. High-impact design elements are needed to make multiparameter optimization efforts more efficient and effective. The exchange of an aromatic methine group with a nitrogen atom is a minor bioisosteric structure modification that can lead to major improvements in a variety of pharmacological parameters. These improvements can enhance the efficiency of multiparameter optimization efforts and increase the probability of success in small molecule drug discovery. In this review, we will discuss general aspects of this structure modification and then highlight twelve case studies in which this design element played a pivotal role in multiparameter optimization efforts, solving key program issues and leading to key tool compounds, pre-clinical candidates, and clinical candidates. [GRAPHICS] .