The conversion of IUPAC's compilations of pKas of organic acids and bases into substructure-searchable data Tony Slater pKaData Limited EuroCUP III Toledo April

Why the interest in pKas? The extent of ionisation of a drug can control :- strength of interaction with receptor protein binding absorption distribution metabolism elimination solubility dissolution rate

An example tuning the pKa of guanidine to affect some of the properties listed in the previous slide

The IUPAC compilation Four books containing pKa data for organic acids and bases in aqueous solution :- Dissociation Constants of Organic Bases in Aqueous Solution, by D. D. Perrin Dissociation Constants of Organic Bases in Aqueous Solution, Supplement 1972, by D. D. Perrin Dissociation Constants of Organic Acids in Aqueous Solution, by G. Kortum, W. Vogel, and K. Andrussow Ionisation Constants of Organic Acids in Aqueous Solution, by E. P. Serjeant and Boyd Dempsey One book containing pKa data for organic acids and bases in non-aqueous solution :- Acid-Base Dissociation Constants in Dipolar Aprotic Solvents (1990); K. Izutsu

pKa measurements for almost compounds in aqueous solution number of measurements considerably higher (eg. some compounds have had their pKa(s) measured at different temperatures and by different authors) fully referenced measurement method recorded temperature recorded remarks field provides more details such as ionic strength, buffer composition etc assessment of data quality is made Whats special about the IUPAC set? "The critical assessment of data quality is one of the major features of this seminal group of pKa compilations for weak organic acids and bases sponsored by the International Union of Pure and Applied Chemistry (IUPAC) from Profiles of Drug Substances, Excipients and Related Methodology Volume 33, 2007, by Richard J. Prankerd, ed Harry G. Brittain

Range of organic chemistry includes :- BASES aliphatic alicyclic aromatic heterocyclic natural products dyes and indicators ACIDS aliphatic carboxylic acids alicyclic carboxylic acids aromatic carboxylic acids phenolic acids other acids dyes and indicators unclassified organic acids Range of Chemistry and Applicability with applicability to :- Pharmaceutical industry Agrochemical industry Specialty Chemicals industry pKa prediction software companies Nb. quality assessment of particular relevance here

Conversion of the Books into Data convert names to smiles supply full reference translate quality assessment into confidence limits supply details of method assign data and text to relevant fields assign temperature to correct field and put other text (eg. ~ or >) in separate field convert pKb into pKa assign non-numeric text (eg. <) to separate field, also assign ion group

Some conversion challenges SMILES 3-bromo-Aniline okay but try these at speed :- 2,3,4,4a,9,9a-hexahydro-2-methyl-9-phenyl-1H-Indeno[2,1-c]pyridine 2-dimethylamino-6,7,8,9-tetrahydro-1(3)H-Naphth[1,2-d]imidazole Mesobiliviolin need to do some research to identify some of the structures If it takes ~ 5 minutes to convert each name into a smiles, then working for 5 hours each day, 5 days a week, with some time off for good behaviour, will require almost a year to produce smiles.

Types of Search Substructure Search for basic pKa with 6.5 < pKa < 7.5 Search for only highest quality data Search for data where 35 ° C temperature 40 ° C Any combination of the above Etc We only supply the data, in suitable format, not the search software, so the types of search possible will depend on your in-house software. This also means that these IUPAC pKa data can be merged with your existing in-house data, with the IUPAC-sourced data clearly identified.

Summary Contacts Website : IUPAC pKa compilations as computer-readable data pKa data for ~12000 organic acids and bases in aqueous solution Very careful assignment of smiles to names by one person Good range of organic chemistry with applicability to pharmaceutical, agrochemical and specialty chemicals research IUPAC assignment of data quality Very useful data set for pKa prediction software Fully referenced with method, temperature, ionic strength etc recorded Careful numeric field assignment for greater search flexibility Ion group assignment for logD calculations and greater search capability Ability to merge with existing in-house data, with IUPAC-sourced data clearly identified