Why pKas Matter in Medicinal Chemistry and a Drug Discovery Amine pKa Table

Drug Hunter Team

In this article, we highlight the importance of pKa values in medicinal chemistry and drug discovery and provide a reference poster of pKa values of common amines’ conjugate bases. Since amines are often a part of marketed drugs, knowledge of their pKas can provide guidance in the selection of basic moieties to match the desired physicochemical properties and biological target of the drug.

What are pKas and Why Do They Matter in Drug Discovery?

In 2007, Manallack published a helpful manuscript outlining the pKa distribution of drugs and how to apply this knowledge to drug discovery. A second publication in 2013 by Manallack, et al. further elaborated on its significance. The pKa of a drug is a key physicochemical property to consider in the drug discovery process given its importance in determining a molecule’s ionization state at physiological pH. Tuning the basicity of an amine and the population of its ionized form in water can impact its:

  • on- and off-target potency (e.g., salt-bridge formation, desolvation penalty)

  • lipophilicity (e.g., LogP vs. LogD)

  • solubility

  • permeability

  • susceptibility to efflux (e.g., Pgp, MDR1)

  • metabolism (e.g., via CYPs, or other enzymes)

  • likelihood of salt formation and salt stability (e.g., during formulation, tableting)

  • and protein binding, among other properties.

Crucially, through a combination of these factors, pKa affects many pharmacokinetic (PK) characteristics of a drug, including absorption, distribution, metabolism, and excretion (ADME).

Amines are highly abundant motifs in drug discovery that play an important role in determining the overall properties of a drug molecule, in part due to the tunability of the pKas of their conjugate bases. Whilst basic centers are attractive features to have in drug molecules for a variety of reasons, including the ability to create water-soluble, crystalline, high melting salts, usually without the plasma protein binding associated with carboxylic acids. However, highly basic compounds can be accompanied by problems including off-target liabilities such as hERG inhibition, CYP inhibition, reduced permeability, susceptibility to efflux, and more.

Drug discovery campaigns will often involve tuning the pKa of an amine’s conjugate base to address drug-like properties (e.g., lowering pKa to address hERG). Some programs will find success in mitigating off-target activity by reducing the basicity of an amine, while others will find success in improving solubility or potency by increasing the basicity of an amine. Knowledge about the trends in amine basicity based on amine substitution can help teams find the right amine for the right problem or determine when an amine may be replaced entirely.

Intro to the Drug Discovery pKa Table and How to Use It

The poster below tabulates the experimental or calculated pKas of amine conjugate bases in water, representative of motifs commonly used in medicinal chemistry. The number in parentheses indicates the experimental or calculated pKa of the conjugate base of each molecule’s basic amine motif. If you already have an ideal pKa for an amine in mind, it can be helpful to start at a fixed horizontal location at the time and scan down the poster to find similarly basic motifs to consider during drug optimization.

This poster is meant to be a practical reference and cannot be comprehensive given the universe of possible substitutions and three-dimensional effects. Experimental data is provided where possible and calculated data are provided where experimental data could not be found. A review of methods of pKa measurement or calculation is beyond to scope of this article but can be found discussed in these reviews.

General Trends in pKas

The poster is organized with more basic amines on the left, and less basic amines on the right, with a cutoff at pH 7 since amines with pKas lower than 7 are unlikely to be meaningfully protonated at physiological pH (~7.4) and further reductions in basicity are unlikely to lead to dramatic property changes based on amine basicity alone (though in certain more acidic compartments like the stomach, lysosomes, or intestinal lumen it may be important). Amines used in drug discovery are frequently made less basic by the addition of heteroatomic functional groups (e.g., fluorination), and rarely made more basic in relevant medicinal chemistry settings. Trends in amine basicity have been reviewed and a slide deck breaking out each subgroup of amines is available for download below.

When and Why pKas Should be Measured

This basic chart helps illustrate general trends, but reality can be much more complex with multiple substituents, 3D environments, stereoelectronic effects, etc. For example, the addition of two methyl groups on N-cyanomethylpiperidine leads to a dramatic change in pKa, likely due to the conformational restriction of the molecule such that the conformation where hyperconjugation between the nitrogen lone pair and C-C sigma* antibonding orbital is possible is much higher in energy.

For this reason, it is important to regularly obtain measured pKa values early in the lead optimization process to understand whether lead molecules are as basic as assumed and to understand the corresponding property changes that accompany changes during medicinal chemistry efforts. Analiza has a high-throughput method to measure pKas and supports companies all over the world in obtaining accurate data using 24-point parallel capillary electrophoresis.


We hope this article and poster are useful to your drug discovery efforts and mentoring your colleagues. If you ever find yourself in need of experimental pKas in the drug discovery process, consider reaching out to our sponsors at Analiza.


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  11. Calculated using the pKa prediction function of PerkinElmer Informatics’ ChemDraw Professional.

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