The pK(a) Distribution of Drugs: Application to Drug Discovery

Abstract

The acid-base dissociation constant (pK(a)) of a drug is a key physicochemical parameter influencing many biopharmaceutical characteristics. While this has been well established, the overall proportion of non-ionizable and ionizable compounds for drug-like substances is not well known. Even less well known is the overall distribution of acid and base pK(a) values. The current study has reviewed the literature with regard to both the proportion of ionizable substances and pK(a) distributions. Further to this a set of 582 drugs with associated pK(a) data was thoroughly examined to provide a representative set of observations. This was further enhanced by delineating the compounds into CNS and non-CNS drugs to investigate where differences exist. Interestingly, the distribution of pK(a) values for single acids differed remarkably between CNS and non-CNS substances with only one CNS compound having an acid pK(a) below 6.1. The distribution of basic substances in the CNS set also showed a marked cut off with no compounds having a pK(a) above 10.5.The pK(a) distributions of drugs are influenced by two main drivers. The first is related to the nature and frequency of occurrence of the functional groups that are commonly observed in pharmaceuticals and the typical range of pK(a) values they span. The other factor concerns the biological targets these compounds are designed to hit. For example, many CNS targets are based on seven transmembrane G protein-coupled receptors (7TM GPCR) which have a key aspartic acid residue known to interact with most ligands. As a consequence, amines are mostly present in the ligands that target 7TM GPCR's and this influences the pK(a) profile of drugs containing basic groups. For larger screening collections of compounds, synthetic chemistry and the working practices of the chemists themselves can influence the proportion of ionizable compounds and consequent pK(a) distributions. The findings from this study expand on current wisdom in pK(a) research and have implications for discovery research with regard to the composition of corporate databases and collections of screening compounds. Rough guidelines have been suggested for the profile of compound collections and will evolve as this research area is expanded.

Keywords: ADME; absorption; acids; ampholytes; bases; bioavailability; dissociation constant; distribution; drug discovery; drugs; pKa; pharmacokinetics.

Figure 1.

Pie charts showing the distribution of acids and bases from the findings of Comer and Tam outlining the survey conducted by Tim Mitchell on the acid base distribution using the 1999 WDI database, (A); the results from the 582 Williams compound dataset, (B); the 174 CNS compound subset, (C); and the 408 non-CNS compound subset, (D). The data associated with these diagrams is given in Tables 1 and 2.

Figure 2.

Chart showing nine acids with a range of pK_a values. In each case the acidic group has been highlighted with an arrow. Penicillin G (1, pK_a = 2.8), Flufenamic acid (2, pK_a = 3.9), Valproic acid (3, pK_a = 4.8), Glipizide (4, pK_a = 5.9), Nitrofurantoin (5, pK_a = 7.1), Pentobarbital (6, pK_a = 8.1), Indapamide (7, pK_a = 8.8), Metolazone (8, pK_a = 9.7), Estrone (9, pK_a = 10.8).

Figure 3.

Histogram showing the pK_a distribution of compounds containing a single acidic group. Each group of columns contains a comparison of the entire set of single acids and those from the CNS and non-CNS subsets. Compounds were binned into 1 log unit ranges. For example, the column listed above 2.5 represents compounds with a pK_a greater than 1.5 and less than or equal to 2.5.

Figure 4.

Chart showing nine bases with a range of pK_a values. In each case the basic group has been highlighted with an arrow. Benzocaine (1, pK_a = 2.5), Diazepam (2, pK_a = 3.4), Cytarabine (3, pK_a = 4.3), Tropicamide (4, pK_a = 5.3), Amiodarone (5, pK_a = 6.6), Droperidol (6, pK_a = 7.6), Loperamide (7, pK_a = 8.6), Atenolol (8, pK_a = 9.6), Naphazoline (9, pK_a = 10.9).

Figure 5.

Diagram showing the pK_a distribution of compounds containing a single basic group. Each group of columns contains a comparison of the entire set of single bases and those from the CNS and non-CNS subsets. Compounds were binned into 1 log unit ranges as per Figure 3.

Figure 6.

Histogram comparing the isoelectric points of both ordinary and zwitterionic ampholytes. In this case the frequencies of the distributions were shown to reflect the differing number of ordinary ampholytes (44 compounds) and zwitterionic ampholytes (21 compounds). Compounds were binned into 1 log unit ranges as per Figure 3.