Pyridyl Boronic Acids for Drug Discovery
Pyridyl boronic acids and esters provide versatile building blocks for constructing pyridyl–aryl and pyridyl–heteroaryl bonds. Pyridines are the most frequently occurring nitrogen heterocycles in new medicines. In an analysis of 321 small molecules approved by the FDA between 2013 and 2023, it overtook piperidine as the most frequently occurring nitrogen heterocycle, and a separate review counted 54 pyridine-containing approvals from 2014 to 2023, with 18 in oncology and 11 in CNS, alongside approvals in rare diseases, haematology and anti-infectives. The pyridyl–aryl and pyridyl–heteroaryl motifs these building blocks deliver are well represented in the clinic. In imatinib and nilotinib, the 3-pyridyl ring is widely described as accepting a hydrogen bond from the kinase hinge, helping anchor both inhibitors in the ATP site of BCR-ABL. Perampanel, an AMPA receptor antagonist for epilepsy, carries a 2-pyridyl substituent on its central pyridone core. Milrinone's 4-pyridyl group forms part of the bipyridine framework of this PDE3 inhibitor for acute heart failure, and atazanavir brings the same motif to HIV protease inhibition through its pyridyl-phenyl unit. Between them, the 2-, 3- and 4-pyridyl isomers cover each of these substitution patterns. Pyridyl boronic acids are valuable tools for a nitrogen scan. The literature on the ‘necessary nitrogen’ effect shows that replacing a single aromatic CH with N can substantially alter potency, solubility, metabolic stability and permeability. One frequently cited example is a Cdc7 kinase inhibitor where replacing a phenyl group with a 4-pyridyl ring improved biochemical activity by more than 500-fold, an effect attributed to a new hydrogen bond with the protein backbone. With a set of pyridyl boronic acid isomers in hand, teams can explore these nitrogen placements in parallel across a series and quickly see which position the target rewards. Results will always depend on the target, but the track record of pyridyl-aryl motifs in approved drugs makes pyridyl boronic acids a natural early addition to any lead optimisation toolkit. 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. A decade of pyridine-containing heterocycles in US FDA approved drugs: a medicinal chemistry-based analysis https://lnkd.in/e\_mzcM8n 2. An Update on the Nitrogen Heterocycle Compositions and Properties of U.S. FDA-Approved Pharmaceuticals \(2013–2023\) https://lnkd.in/eiiQU5Mw 3. Harnessing the necessary nitrogen atom in chemical biology and drug discovery https://lnkd.in/eAdzNc97