QSAR and the rational design of long-acting dual D2-receptor/β2-adrenoceptor agonists

被引：52

作者：

Austin, RP ^{[1
]}

Barton, P ^{[1
]}

Bonnert, RV ^{[1
]}

Brown, RC ^{[1
]}

Cage, PA ^{[1
]}

Cheshire, DR ^{[1
]}

Davis, AM ^{[1
]}

Dougall, IG ^{[1
]}

Ince, F ^{[1
]}

Pairaudeau, G ^{[1
]}

Young, A ^{[1
]}

机构：

[1] AstraZeneca R&D Charnwood, Loughborough LE11 5RH, Leics, England

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2003年 / 46卷 / 15期

关键词：

D O I：

10.1021/jm020886c

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

This paper describes the development of a QSAR model for the rational control of functional duration of topical long-acting dual D-2-receptor/beta(2)-adrenoceptor agonists for the treatment of chronic obstructive pulmonary disease. A QSAR model highlighted the importance of lipophilicity and ionization in controlling beta(2) duration. It was found that design rules logD(7.4) > 2, secondary amine pK(a) > 8.0, yielded ultra-long duration compounds. This model was used successfully to guide the design of long- and ultra-long-acting compounds. The QSAR model is discussed in terms of the exosite model, and the plasmalemma diffusion microkinetic hypothesis, for the control of beta(2) duration. Data presented strongly suggests that beta(2) duration is primarily controlled by the membrane affinity of these compounds.

引用

页码：3210 / 3220

页数：11