The document discusses replacing benzene rings with heterocyclic rings and assessing their impact on various absorption, distribution, metabolism, excretion, and toxicity (ADME/T) properties using matched molecular pair analysis. It finds that the influence on the ADME/T profile can differ significantly depending on the specific heterocyclic ring and its individual regioisomers. This information allows medicinal chemists to choose ring replacements that are likely to influence ADME/T properties in a desired way, such as increasing solubility without cytochrome P450 liability.

1. Heterocyclic replacements for benzene: Maximising ADME benefits by
considering individual ring isomers
• The impact of replacing a mono-
substituted benzene (phenyl) ring with
thirty three aromatic and nine aliphatic
heterocycles on nine ADME-related
screens (solubility, lipophilicity,
permeability, protein binding CYP450
inhibition and metabolic clearance) was
assessed using matched molecular pair
analysis.
• The results indicate that the influence
on the ADME profile can differ
significantly depending on the ring
identity and importantly on the individual
regioisomers that are possible for some
rings.
• This information enables the medicinal
chemist to make an informed choice
about which rings and regioisomers to
employ as mono-substituted benzene
replacements, based upon the
knowledge of how such replacements
are likely to influence ADME-related
parameters, for example to target higher
solubility whilst avoiding CYP450
liabilities.
• Full article: Eur J Med Chem 2016, 124, 1057. DOI: 10.1016/j.ejmech.2016.10.029 T J Ritchie
Replacing benzene with nitrogen-containing aromatic
heterocycles: effect on nine ADME properties
(matched molecular pair analysis)

2. Insights into the impact of N- and O-methylation on aqueous solubility and
lipophilicity using matched molecular pair analysis
• The impact of N- and O-methylation on
chromatographically measured lipophilicity and
high throughput aqueous solubility was studied
using matched molecular pairs for data sets of
amides, sulfonamides, ureas, carbamates,
amines, carboxylic acids, alcohols and phenols.
• The extent to which solubility and lipophilicity are
affected by N- or O-methylation is dependent on
the nature of atoms and substituents around the
nitrogen or oxygen atom. In some classes of
amides, N-methylation unexpectedly increases
solubility and lowers logD7.4 considerably: this
behaviour can be rationalised by conformational
changes accompanying N-methylation that
increase polar surface area, or by the disruption
of one or more intramolecular hydrogen bonding
motifs.
• Unlike amides, sulfonamide N-methylation
always reduces solubility and increases
lipophilicity, which again can be understood in
terms of conformational effects.
• As expected, methylation of carboxylic acids
lowers solubility and increases lipophilicity due to
masking of the ionisable acidic group; however
the magnitude of the reduction in solubility
depends to some extent on the lipophilicity and
molecular weight of the compound pairs under
investigation.
• Full article: Med Chem Commun 2015, 6, 1787. DOI: 10.1039/c5md00309a T J Ritchie
Disruption of intramolecular H-bonding by amide N-
methylation can increase solubility and decrease logD
N-methylation
increases
solubility and
decreases logD
N-methylation
has no effect
on solubility
and logD

3. Physicochemical descriptors of aromatic character and their
use in drug discovery
Published physicochemical descriptors of molecules that convey aromaticity-related character are
reviewed in the context of drug design and discovery. Studies that have employed aromatic descriptors
are discussed, and several descriptors are compared and contrasted.
• Full article: J Med Chem 2014 DOI: 10.1021/jm500515d T J Ritchie

4. How drug-like are ‘ugly’ drugs?
Drugs with high QED scores exhibit higher absorption and bioavailability, are
administered at lower doses and have fewer drug–drug interaction warnings, P-
glycoprotein interactions and absorption issues due to a food effect. By contrast,
the high-scoring drugs exhibit similar behaviour to low-scoring drugs with
respect to free fraction in plasma, extent of gut-wall metabolism, first-pass
hepatic extraction, elimination half-life, clearance, volume of distribution and
frequency of dosing.
• Full article: Drug Discovery Today 2014, 19, 489 T J Ritchie
Using a published drug-likeness score based on the calculated physicochemical properties of marketed oral
drugs (quantitative estimate of drug-likeness, QED) and published human data, high-scoring and low-scoring
drugs were compared to determine how well the score correlated with their actual pharmaceutical and
pharmacokinetic (PK) profiles in humans.

5. Increasing small drug molecule developability in sub-optimal
chemical space
• Full article: Med Chem Commun, 2013, 4, 673
Using compounds occupying four distinct clogP / molecular weight regions that define optimal and sub-
optimal chemical space, and a developability score derived from solubility, permeability, protein binding
and 3A4 inhibition screening data, OPLS regression models were constructed to determine which
physico-chemical properties were most correlated with developability. The results suggested that whilst
certain molecule properties were important for developability across all chemical space, such as [clogD
+ aromatic ring count], [clog D + (aromatic atom count – sp3 carbon count)] and [sp3 carbon count /
total carbon count], others such as heteroaliphatic ring count, positive ionisable group count and H-
bond donor character exhibited varying degrees of importance depending on the clogP / MW region.
T J Ritchie
Green = high developability
Yellow = medium developability
Red = low developability

6. The developability of heteroaromatic and heteroaliphatic rings
• Full article: Med Chem Commun, 2012, 3, 1062.
Heteroaliphatic Solubility HSA binding P450 inhib. Combined score ChromLogD
Piperidine NH 3 3 3 3.0 3.56
Morpholine NAlk 3 3 3 3.0 4.89
Imidazolidine 2 3 3 2.7 4.27
Piperidine NAlk 2 2 3 2.3 5.09
Pyrrolidine NAr 2 2 3 2.3 4.39
Piperazine 2 2 2 2.0 4.81
Morpholine NAr 2 2 2 2.0 5.3
Pyrrolidine NCO 2 2 2 2.0 5.43
Piperidine NAr 2 2 2 2.0 4.66
Piperidine NCO 2 2 1 1.7 5.27
Tetrahydrofuran 1 2 2 1.7 6.13
Pyrrolidine NAlk 2 2 1 1.7 5.23
Morpholine NSO2 2 1 2 1.7 5.72
1,3-Thiazolidine 1 1 1 1.0 5.46
Pyrrolidine NSO2 1 1 1 1.0 6.08
Piperidine NSO2 1 1 1 1.0 6.24
Aqueous solubility, protein binding and CYP450 inhibition data for compounds containing a variety of
heteroaromatic and heteroaliphatic rings were analysed and compared to determine which ring types
fared best and worst in these developability screens. The results suggest that certain heterorings are
generally more developable than others: how this information may be used and some caveats to be
borne in mind are discussed.
T J Ritchie

7. The graphical representation of ADME-related properties
T J Ritchie
• Full review article: Drug Discovery Today, 2011, 16, 65-72

8. The Impact of aromatic ring count on compound developability
–are too many aromatic rings a liability in drug design?
• Full review article: Drug Discovery Today, 2009, 14, 1011-1020
T J Ritchie

9. The Impact of aromatic ring count on compound developability:
Further insights by examining carbo- and hetero- ring types
• Full review article:
Drug Discovery Today, 2011, 16, 164-171
T J Ritchie
The impact of aromatic and aliphatic ring counts on
several developability measures (solubility, lipophilicity,
protein binding, P450 inhibition and hERG binding)
indicate that increasing ring counts have detrimental
effects on developability in the order carboaromatics >>
heteroaromatics > carboaliphatics > heteroaliphatics,
with heteroaliphatics exerting a beneficial effect in
many cases.

10. Analysis of the calculated physicochemical properties of
respiratory drugs
• Full article: J. Chem. Inf. Model. 2009, 49 (4), 1025-1032
T J Ritchie
From an analysis of calculated physicochemical
properties for 81 currently marketed respiratory drugs,
compounds administered via the inhaled/intranasal
routes have a higher polar surface area, a higher
molecular weight, and a trend toward lower lipophilicity,
when compared with their orally administered
counterparts. Ranges of physicochemical space are
described for the 29 drugs administered by the inhaled
or intranasal routes.