Physicochemical properties have been shown to be important in many areas of drug design, potency, QSAR, off-target activity, ADME, solubility and formulation. Most properties can be calculated but some more accurately than others. There are a number of websites that offer physicochemical property calculations but be cautious submitting proprietary information.

pKa

It has been reported that most drugs are ionized in the range of 60-90% at physiological pH [DOI]. Difficult to calculate accurately, there are a few sites that give experimentally determined data.  Drug-like molecules present difficulties for pK_a prediction compared with simple monoprotic molecules. They are often multiprotic, have large conjugated systems, contain heterocycles, can tautomerize. In addition, drug-like molecules with significant conformational flexibility can form intramolecular hydrogen bonding, which can significantly shift their pK_a values compared to simple monoprotic molecules.

ChemAxon has a pKa plugin, the Plugin calculates the values of the molecule based on its partial charge distribution. It also displays ionisation distribution and can allow for tautomerisation.

Rowan uses machine learning-based interatomic potentials to vastly accelerate the accurate calculation of pK_a values.

ACD/labs algorithms have been in development since 2003 and the latest version uses a database of >15,000 experimental values

QupKake QupKake combines GFN2-xTB calculations with graph-neural-networks to accurately predict micro-pKa values of organic molecules.

OPERA is an open-source command line application that uses PaDEL and CDK descriptors

pKasolver is a package that enables prediction of pKa values of small molecules via graph convolutional networks with Dimorphite-DL, an open-source program for enumerating ionization states.

BCL-XpKa  a deep neural network (DNN)-based multitask classifier for pK_a prediction that encodes local atomic environments through Mol2D descriptors

pKa Data Compiled by David Ripin and David Evans (Harvard University) Bordwell pKa Table Acidity in DMSO (Univ. of Wisconsin) Zirchrom list of over 600 acids and bases

See Also:- Dissociation constants of organic bases in aqueous solution. D.D. Perrin. Butterworths, 1965. Dissociation constants of organic acids in aqueous solution. G.Kortum, W.Vogel and K.Andrussow. Butterworth, 1961.

Tuning the basicity of amines

Whilst basic centers are attractive features to have in drug molecules because they offer the ability to create water soluble, crystalline, high melting salts, usually without the plasma protein binding associated with carboxylic acids. They can cause problems with HERG, CYP450 2D6.

However it is possible to tune the pKa of the basic center and thus modulate the properties of the molecule. Whilst primary and secondary amines are more basic than tertiary increasing alkyl substitution does usually increase basicity.

Usually however you will be looking to reduce basicity, this is best achieved by heteroatom substitution, in particular by replacing a hydrogen with fluorine since this will have little steric impact. The chart below shows the impact of adding fluorine atoms the influence of which can be observed through several bonds. Similar effects can be seen in cyclic amines, however the effect is influenced by the conformation of the ring with the equatorial fluorine having the greater effect. It should be noted that these changes may have a detrimental effect of lipophilicity.

The basicity of the piperidine nitrogen can also be modulated by moving to the morpholine or N-substituted piperazine, particularly when the nitrogen is substituted by acyl or sulphonyl groups. Similar effects can be seen in acyclic systems where a beta hydroxy or alcoxy group will reduce the pka by 1.2 units, and similar substituents at the gamma position by -0.8 units.

Strongly electron-withdrawing groups like nitriles, esters, amides, ketones, oxetanes and polyheteroatom hetrocycles e.g. oxadiazoles, can also be used to modulate pKa but they do introduce further pharmacophoric elements. An interesting paper by Wuitschik et al looks at oxetanes as replacements for carbonyl and how they might influence physicochemical properties, whilst a variety of different structures are compared I’ve just pulled out the data for 4-substituted piperidines. Whilst the influence on pKa is intermediate between piperidine and the corresponding 4-piperidone the more polar oxetane means that the resulting LogD is actually lower.

The influence of fluorine’s impact on pKa and in vitro PGP-mediated efflux for a series of PDE9 inhibitors (below) has been explored DOI. Introduction of fluorine impacted both the basic amine but also the acidity of the lactam. Comparisons through the series of compounds and their fluorinated analogues reveals a systematic decrease in acidic pKa between 1.2–1.7 (pKa (acidic)), and shifts for the basic pyrrolidines between 1.1–3.3 units (pka basic). Introduction of F into the NH lactams often served to increase PGP activity, in contrast introduction into the N-Methyl lactams reduced PGP activity.

Modulation of the pKa of a basic amine can have multiple beneficial effects. In the example below DOI reducing the basicity of the piperidine nitrogen reduces hERG activity and also reduces clearance.

Basicity of Guanidines

The guanidine group is highly basic (pKa 13.6 in water), the additional hydrogen bonding capabilities also make this an interesting functional group for drug design.

The substituent effects on the basicity (pKa) of aryl guanidines and 2-(arylimino)imidazolidines has been studied [DOI].