The impact of aromatic ring count on compound developability: further insights by examining carbo- and hetero-aromatic and -aliphatic ring types

详细信息    查看全文

• 作者：Timothy J. Ritchie¹ ; ^{tim.j.ritchie@gmail.com} ; Simon J.F. Macdonald² ; ^{simon.jf.macdonald@gsk.com} ; Robert J. Young³ ; Stephen D. Pickett⁴
• 刊名：Drug Discovery Today
• 出版年：2011
• 出版时间：February 2011
• 年：2011
• 卷：16
• 期：3-4
• 页码：164-171
• 全文大小：891 K

文摘

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.