The impact of N-methylation on aqueous solubility and lipophilicity


N-Methylation is a common transformation used by medicinal chemists in drug discovery programs. This small transformation, which only adds 14 units of molar mass, can be carried out to improve the pharmacological effect of a compound by filling an additional pocket in an enzyme binding site or to mask a hydrogen bond donor responsible for a poor DMPK property. For instance, hydrogen bond donors can drive transporters recognition and their removal can significantly improve compound absorption. However, this small chemical modification often induces a change in other physicochemical properties of the drug such as clearance, aqueous solubility and lipophilicity.

Using matched molecular pair analysis, a team of scientist at GSK highlighted the effect of methylating heteroatoms on measured CLND aqueous solubility and lipophilicity (Med. Chem. Commun., 2015, 6, 1787-1797). All experimental CLND solubility and chromatographic log D data were collected from GSK in-house dataset. As a medicinal chemist working on a lead optimisation project and trying to balance pharmacological potency with physicochemical properties, I found this information of considerable value and thought that it would be useful to share it with my fellow medicinal chemists.

The analysis conducted by the authors reveals that overall N-methylation of secondary amides leads to an increase in log solubility despite a concomitant increase in log D. However, three distinct classes of secondary amides can be distinguished. Upon N-methylation, amides derived from aliphatic acids show a small increase in solubility and higher log D, whereas amides from aromatic acids exhibit a more pronounced solubility increase and less impact on log D. In the case of amides derived from aromatic acids and anilines, the solubility increase is accompanied by a significant log D reduction. This is explained by a change in the conformation of the compound upon N-methylation. The variation in the C-C-N-C torsion angle indicates a switch from Z- to E-amide geometry. Despite the loss of the polar NH and addition of a hydrophobic methyl group, the loss of planarity increases water-accessible polar surface area, leading to higher solubility and lower lipophilicity. N-methylation of primary aliphatic and aromatic amides has little effect on solubility but increases lipophilicity. N-methylation of cyclic secondary amide does not increase solubility but induces a pronounced increase in log D, indicating that in this case there is no conformational modification but simply the replacement of a polar hydrogen by a hydrophobic methyl.

Amide NH can be part of intramolecular hydrogen bonds with a suitable acceptor at proximity. The majority of molecules with such motifs adopt planar conformations which have impact on physical properties, such as membrane permeability, protein binding, aqueous solubility and lipophilicity. N-methylating amides with intramolecular H-bonds generally induce an increase in solubility and a log D decrease, although the magnitude of these effects depends on the type of intramolecular H-bond.

In contrast to amides, the N-methylation of sulfonamides results in a more expected behavior, with an increase in log D and decrease in solubility. The rationale behind this behavior is that N-methylation of sulfonamides has little impact on conformation. Addition of the hydrophobic methyl decreases polar surface area and hence increases lipophilicity and decrease solubility. The sulfonamide NH can also have an acidic pKa, being partially deprotonated at physiological pH and masking this solubilizing moiety increases lipophilicity and lowers solubility.

Ureas are known to hamper the solubility of drug molecules. This analysis of the GSK dataset revealed that methylation of ureas derived from anilines appears to increase solubility considerably, to a larger extent than what was observed for amides. Upon N-methylation, aromatic ureas gain conformational freedom, leading to increase solubility despite an increase in lipophilicity.

N-methylation of secondary amines has little impact on solubility but log D increases, independently on their structure. A small reduction in basicity is also observed with a reduction of pKa of 1 unit for the amine nitrogen upon methylation.

The effect of O-methylation is also described and gives very predictive results with a significant increase in lipophilicity and a concomitant decrease in solubility. This effect is more pronounced when the transformation is carried out on carboxylic acids. However, this transformation is not of interest for medicinal chemists since introduction of esters in drug molecules is undesired.

Figure 1: Scatter plot summarising the impact of N-methylation on aqueous solubility and lipophilicity for a variety of substrate

Figure 1: Scatter plot summarising the impact of N-methylation on aqueous solubility and lipophilicity for a variety of substrate

The conclusion form this study is that a small change in structure such as a methylation can lead to profound changes in conformation and physical properties. Depending on the substrate, N-methylation can have opposite effect on solubility and lipophilicity (Figure 1). The results emphasize the importance of the local chemical environment around the methylation heteroatom.

Blog written by Tristan Reullion

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