The Magic Methyl and Its Tricks in Drug Discovery and Development

Abstract

One of the key scientific aspects of small-molecule drug discovery and development is the analysis of the relationship between its chemical structure and biological activity. Understanding the effects that lead to significant changes in biological activity is of paramount importance for the rational design and optimization of bioactive molecules. The "methylation effect", or the "magic methyl" effect, is a factor that stands out due to the number of examples that demonstrate profound changes in either pharmacodynamic or pharmacokinetic properties. In many cases, this has been carried out rationally, but in others it has been the product of serendipitous observations. This paper summarizes recent examples that provide an overview of the current state of the art and contribute to a better understanding of the methylation effect in bioactive small-molecule drug candidates.

Keywords: drug design; magic methyl; methyl; methyl effect; methylation; methylation effect.

Figure 1

The discovery of anticancer FDA-approved drug tazemetostat (8) [16].

Figure 2

The methylation effect in the discovery of EZH2-selective inhibitors [19].

Figure 3

The methylation effect in the design of PI3K/mTOR inhibitors [20].

Figure 4

The methylation effect in the discovery of selective κ opioid receptor antagonists [26].

Figure 5

Design of oxazolo[5,4-d]pyrimidines series as new CB1/CB2 receptor modulators [29].

Figure 6

Design of selective CB₂R agonists as potential agents for the treatment of skin inflammatory disease [31].

Figure 7

Methylation effect on the design of modulators for CB₁R [32].

Figure 8

Methylation effect on fragment-like discovery of H₁R antagonists [37].

Figure 9

Fragment-based drug discovery of phosphopantetheine adenylyltransferase inhibitors [38].

Figure 10

The methylation effect in fragment optimization [38].

Figure 11

The methylation effect in polyploidy-inducing activity correlated to genetic depletion of AURKB [40].

Figure 12

Methylation effect in the discovery of antagonists of the neurokinin-3 receptor (NK3R) [42].

Figure 13

The methylation effect in new cereblon ligands for targeted protein degradation [45].

Figure 14

The methylation effect in combretastatin A-4 analogs [46].

Figure 15

The methylation effect stabilizing bioactive conformation of multitarget N-acylhydrazone derivatives [50].

Figure 16

The methylation effect in the design of PDE4D inhibitors [52].

Figure 17

Exploration of the methylation effect for the discovery of selective PDE4A and PDE4D inhibitors [53].

Figure 18

The methylation in N-sulfonylhydrazone derivatives [57].

Figure 19

Ligands of Toll-like Receptor 4/Myeloid Differentiation Protein 2 complex [60].

Figure 20

The methylation effect in the discovery of ulimorelin (73) [65].

Figure 21

The methylation effect on NS3/4A protease inhibition for the treatment of hepatitis C virus infection [66].

Figure 22

The methylation effect in the discovery of macrocyclic Class I HDAC inhibitors [68].

Figure 23

The methylation effect in the design of trypanocidal agents [70].

Figure 24

Design of sulfonylhydrazone derivatives as antibacterial agents [72].

Figure 25

Evaluation of bis-(3-indolyl)methane phosphonate derivatives as anticancer agents [73].

Figure 26

Methylation effect in N-acylhydrazone derivatives for aqueous solubility optimization [74].

Figure 27

The use of the methylation effect for plasma stability optimization [76].

Figure 28

The exploration of the methylation effect for hERG inhibition profile optimization of CHK1 inhibitors [77].

Figure 29

The methylation effect in hERG inhibition profile optimization of mu opioid ligands [78].

Figure 30

Metabolic profile optimization using the methylation effect [80].