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

被引：341

作者：

Ritchie, Timothy J. ^{[1
]}

Macdonald, Simon J. F. ^{[2
]}

Young, Robert J. ^{[3
]}

Pickett, Stephen D. ^{[3
,4
]}

机构：

[1] TJR Chem, I-21020 Ranco, VA, Italy

[2] GlaxoSmithKline Med Res Ctr, Resp CEDD, Stevenage SG1 2NY, Herts, England

[3] GlaxoSmithKline Med Res Ctr, Dept CSC Med Chem, Stevenage SG1 2NY, Herts, England

[4] GlaxoSmithKline Med Res Ctr, Computat & Struct Chem, Stevenage SG1 2NY, Herts, England

来源：

DRUG DISCOVERY TODAY | 2011年 / 16卷 / 3-4期

关键词：

ORAL BIOAVAILABILITY; DRUG DISCOVERY;

D O I：

10.1016/j.drudis.2010.11.014

中图分类号：

R9 [药学];

学科分类号：

1007 ;

摘要：

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.

引用

页码：164 / 171

页数：8

共 17 条

[1] HERG binding specificity and binding site structure: evidence from a fragment-based evolutionary computing SAR study [J].