The impact of aromatic ring count on compound developability--are too many aromatic rings a liability in drug design?
The impact of aromatic ring count (the number of aromatic and heteroaromatic rings) in molecules has been analyzed against various developability parameters - aqueous solubility, lipophilicity, serum albumin binding, CyP450 inhibition and hERG inhibition. On the basis of this analysis, it was concluded that the fewer aromatic rings contained in an oral drug candidate, the more developable that candidate is probably to be; in addition, more than three aromatic rings in a molecule correlates with poorer compound developability and, thus, an increased risk of attrition in development. Data are also presented that demonstrate that even within a defined lipophilicity range, increased aromatic ring count leads to decreased aqueous solubility.
Ritchie
Timothy J
TJ
Respiratory CEDD, GlaxoSmithKline Research Medicines Centre, Gunnels Wood Road, Stevenage SG1 2NY, UK.
Macdonald
Simon J F
SJ
D002257:Carbonic Anhydrase Inhibitors; D051544:Cytochrome P-450 CYP3A; D065692:Cytochrome P-450 CYP3A Inhibitors; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000494:pharmacology; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors; D006801:Humans; D006841:Hydrocarbons, Aromatic / Q000737:chemistry* / Q000493:pharmacokinetics; D007408:Intestinal Absorption; D008055:Lipids / Q000737:chemistry; D049449:Luminescence; D026902:Potassium Channel Blockers / Q000494:pharmacology; D011485:Protein Binding; D012709:Serum Albumin / Q000378:metabolism; D012995:Solubility; D013329:Structure-Activity Relationship
D002257:Carbonic Anhydrase Inhibitors; D065692:Cytochrome P-450 CYP3A Inhibitors; D004791:Enzyme Inhibitors; D051638:Ether-A-Go-Go Potassium Channels; D006841:Hydrocarbons, Aromatic; D008055:Lipids; D026902:Potassium Channel Blockers; D012709:Serum Albumin; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human