Pharmacophore, drug metabolism, and pharmacokinetics models on non-peptide AT1, AT2, and AT1/AT2 angiotensin II receptor antagonists
Pharmacophore, drug metabolism, and pharmacokinetics models on non-peptide AT1, AT2, and AT1/AT2 angiotensin II receptor antagonists
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DOI：
10.1021/jm049024x
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发表时间：
2005-06-30
影响因子：
7.3
通讯作者：
Mannhold, R
中科院分区：
文献类型：
--
作者：
Berellini, G;Cruciani, G;Mannhold, R
大约有20种非肽类血管紧张素II受体拮抗剂正处于不同的临床开发阶段。不同的建模方法被用来预测AT(1)(血管紧张素II受体亚型1)亲和力的药理需要。然而，据我们所知，没有一种方法同时用于预测AT(1)和AT(2)(血管紧张素II受体亚型2)受体亚型的选择性。本文应用偏最小二乘判别分析，推导出指导AT(1)和AT(2)选择性或AT(1)/AT(2)混合受体结合的化学特征。该方法可用于调节AT(1)与AT(2)的选择性。对AT(2)受体的非对抗性刺激可能产生不良影响的担忧引发了对新的平衡拮抗剂的研究。此外，它还可以作为数据库搜索的快速过滤程序。最后，使用VolSurf和MetaSite软件计算了包含53个化合物的数据库的一些相关的药代动力学和代谢性质，以便同时表征血管紧张素II受体拮抗剂的化学空间的药效学和药代动力学性质。
About 20 non-peptide angiotensin II receptor antagonists are in various stages of clinical development. Different modeling approaches were used to predict the pharmacophoric requirements for AT(1) (angiotensin II receptor subtype 1) affinity. However, to our knowledge, none was used to predict both the selectivity toward AT(1) and AT(2) (angiotensin II receptor subtype 2) receptor subtypes. In this paper, partial least squares discriminant analysis is applied to derive the chemical features guiding AT(1) and AT(2) selectivity or mixed AT(1)/AT(2) receptor binding. The method can be used to modulate AT(1) versus AT(2) selectivity. Concerns that unopposed stimulation of the AT(2) receptor might produce adverse effects initiated a search for new balanced antagonists. Moreover, it can serve as a fast filtering procedure in database searches. Finally, some relevant pharmacokinetics and metabolic properties of the database of 53 compounds are calculated using the VolSurf and MetaSite software to allow the simultaneous characterization of pharmacodynamic and pharmacokinetics properties of the chemical space of angiotensin II receptor antagonists.