In this article from 2011, Ritchie et al. review the detrimental effects of increasing aromatic ring count on several developability measures such as solubility, lipophilicity, protein binding, P450inhibition and hERG binding.
The fewer the number of aromatic rings contained in an oral drug candidate, the more developable that candidate is likely to be, and that more than three aromatic rings in a molecule correlate with poorer compound developability (increased risk of compound attrition)
The sum of aromatic ring count andclogD7.4 has now been used as a simple but effective indicator of the solubility category. A new parameter, aromatic atom count – sp3 atom count (Ar-sp3), which describes aromatic/aliphatic balance, has also been introduced recently in an analysis of oral drugs and patented medicinal chemistry compounds.
Carboaromatics and and benzo-fused ring systems are inherently lipophilic and have strong deleterious effects on developability by
- lowering aqueous solubility
- increasing lipophilicity (CHI log D 7.4)
- increasing HSA and AGP binding.
- negative effects on CyP 3A4, 2C9, 2C19 and hERG inhibition.
- A small beneficial effect (a reduction) was observed in CyP 1A2 binding as the carboaromatic ring count increased, presumably because of the size limitation of the narrow, planar active site in this enzyme
The consequences of increasing heteroaromatic ring count, although not as dramatic as seen with carboaromatics, resulted in:
- lower aqueous solubility,
- increased HSA binding
- increased CyP 3A4 and 2C9 inhibition.
- no effect on AGP binding, CyP 2C19 inhibition or hERG binding
- reduction in CHI logD7.4;this might be expected to result in higher solubility but in reality this appears to be negated by the addition of a planar ring.
Increasing carboaliphatic ring count had little impact on developability measures, although there was a modest increase in lipophilicity.
Increasing heteroaliphatic ring count improved developability by
- increasing solubility
- lower lipophilicity,
- lower HSA binding
- reduce CyP, 2c9, 2c19 and 1a2inhibition.
- no effect on AGP binding, CyP 3A4 inhibition
- increases molecular weight (MW) (presumably owing to the increase in six-membered rings and the additional positions available for substitution on carbon rings)
- increase lipophilicity (DaylightclogP and CHI logD7.4),
- reduced aqueous solubility, higher protein binding and CyP450 inhibition
- hERG binding also increased although the effects were less dramatic but still statistically significant, except for CyP 1A2 inhibition.
When this analysis was repeated for compounds with a total of four aromatic rings, a similar pattern of deterioration in developability was observed as the proportion of carboaromatic content increased relative to heteroaromatic content.
Thus, based on this analysis the authors recommend a replacement of carboaromatic rings with heteroaromatic rings where possible. A recent survey also suggested that many synthetically tractable heteroaromatic ring systems have yet to be synthesized.