The impact of aromatic ring count on compound developability: further insights by examining carbo- and hetero-aromatic and -aliphatic ring types.
The impact of carboaromatic, heteroaromatic, carboaliphatic and heteroaliphatic ring counts and fused aromatic ring count on several developability measures (solubility, lipophilicity, protein binding, P450 inhibition and hERG binding) is the topic for this review article. Recent results 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. Increasing aromatic ring count exerts effects on several developability parameters that are lipophilicity- and size-independent, and fused aromatic systems have a beneficial effect relative to their nonfused counterparts. Increasing aromatic ring count has a detrimental effect on human bioavailability parameters, and heteroaromatic ring count (but not other ring counts) has increased over time in marketed oral drugs.
TJR-Chem, Via Alberto 34C, 21020 Ranco, VA, Italy. tim.j.ritchie@gmail.com
Timothy J
TJ
Ritchie
Simon J F
SJ
Macdonald
Robert J
RJ
Young
Stephen D
SD
Pickett
D000284:Administration, Oral; D015195:Drug Design; D006571:Heterocyclic Compounds / Q000138:chemical synthesis / Q000737:chemistry*; D006801:Humans; D006841:Hydrocarbons, Aromatic / Q000138:chemical synthesis / Q000737:chemistry*; D040541:Marketing / Q000706:statistics & numerical data; D004364:Pharmaceutical Preparations / Q000008:administration & dosage / Q000138:chemical synthesis / Q000737:chemistry*; D010599:Pharmacokinetics; D012995:Solubility; D013329:Structure-Activity Relationship
D006571:Heterocyclic Compounds; D006841:Hydrocarbons, Aromatic; D004364:Pharmaceutical Preparations