The Necessary Nitrogen Atom

In the modern drug discovery process, medicinal chemists strive for high-impact design elements during multiparameter optimisation of lead compounds into efficacious drug candidates. One of such well-known design elements, often referred to as “the magic methyl effect”, “the methyl walk” or “the methyl scan”, involves a replacement of a H atom with a Me group and, as the result, can lead to profound potency improvement (>100-fold).

The authors of the recently published perspective (DOI: 10.1021/acs.jmedchem.6b01807) discuss another common design element for multiparameter optimisation: substitution of a CH group with a N atom in aromatic and heteroaromatic ring systems. Such replacement, when going from a simple benzene ring to pyridine, results in profound changes in molecular and physicochemical properties, such as distribution of electron density, polar surface area, basicity, which in turn affects lipophilicity and solubility. In more complex chemical structures, these changes can impact upon a number of intra- and intermolecular, orbital, steric, electrostatic, and hydrophobic interactions, such as lone pair, dipole−dipole, hydrogen bonding, metal coordination, van der Waals, σ-hole, σ*S−X, and π-system interactions, which in turn can translate into modified pharmacological profiles.

The authors then illustrate an extensive number of drug discovery case studies from the recent literature, where a replacement of a CH group with a N atom resulted in ≥10-fold improvement in at least one key pharmacological parameter, as shown, for example, in Figure 1. The replacement of the C7 CH group in (1) with a N atom to give (2) resulted in a 300-fold improvement in biochemical potency, Cdc7 IC50 = 2700 and 9.0 nM for (1) and (2), respectively. This potency improvement was attributed to the different conformational preferences of the two analogues. The biaryl dihedral angle of >150° in indole (1) greatly differs from that of aza-indole (2) (dihedral angle of 0°), facilitated by a steric clash of H7 and H6′ in (1) and lone pair repulsion between N7 and N2′ in (2).


Figure 1. An example of a necessary nitrogen atom on potency improvement, likely due to different conformational preferences.

The effects of such replacement on basicity, lipophilicity, polar surface area, and hydrogen bonding capacity are relatively predictable; whereas effects on aqueous solubility, passive permeability, efflux profiles, active transport, protein binding, and metabolic stability can be more whimsical and counterintuitive. In some examples, no rational explanation could be given for the observed effect.

With regards to changes in potency, as the authors are cautious to point out, there is an approximately equal probability of increasing or decreasing potency by exchanging CH groups and N atoms, based on a matched molecular pair analysis (MMPA) of available data. However, these findings are very similar to those discussed for the magic methyl effect.

This perspective is not a manual for what pharmacological improvements will be realized upon the substitution of a CH group with a N atom, but rather as an extensive exemplar of the dramatic improvements that can be achieved under certain circumstances. The systematic N atom scan (N-scan) should be exploited where appropriate, particularly in cases where the preferred binding pose of the ligand is not known.

Some recommendations for the N-scan tactics are summarised below. The newly installed N atom might:

  1. Engage in a hydrogen bond with specific residues of the target receptor or receptor-bound water molecules that need to be satisfied
  2. Remove unfavorable van der Waals interactions the replaced CH group made with the target receptor
  3. Form unfavorable electrostatic interactions with an antitarget receptor
  4. Have a positive effect on the binding conformation of the ligand
  5. Mask a hydrogen bond donor in the ligand
  6. Reduce the basicity or HBA strength of an existing N atom in the ligand
  7. Evenly distribute the polar surface area of the ligand
  8. Properly tune the lipophilicity of the ligand
  9. Be shielded by other substituents or functionality in the ligand
  10. Stabilize chemically labile functionality in the ligand
  11. Replace a metabolically labile CH group in the ligand

Medicinal chemists have to constantly juggle the design of biologically active molecules with drug-like properties according to the rules of Lipinski and Veber, in order to achieve good permeability and absorption levels, which in turn lead to high oral bioavailability. These properties are particularly important when considering therapeutic targets located in the central nervous system (CNS) behind the blood−brain barrier (BBB). Keeping the number of hydrogen bond acceptors down is one of such requirements; however, in some cases, it may turn out that the introduction of one (or two) extra N atoms may be necessary.

Blog written by Irina Chuckowree



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