title: A risk assessment of human ether-a-go-go-related gene potassium channel inhibition by using lipophilicity and basicity for drug discovery.
abstract: The blockade of human ether-a-go-go-related gene (hERG) potassium channels is widely regarded as the predominant cause of drug-induced QT prolongation. The correlation analysis between the inhibition of the hERG channel (hERG inhibition) and physicochemical properties was investigated by use of in-house quinolone antibiotics as model compounds. In order to establish a simple prediction model of hERG inhibition, we focused on the comprehensible physicochemical parameters such as lipophilicity (log P) and basicity (pK(a)). At first, the risk associated with increasing log P and pK(a) was examined by statistical analysis. It was demonstrated that the risk associated with increasing log P and pK(a) by one unit, respectively, almost identically increased. Consequently, equal attention should be paid to both parameters on hERG inhibition. Next, a prediction model of hERG inhibition which was represented by log P and pK(a) was investigated. As a result, we built the stepwise discriminant prediction model which took advantage of the risk judgment by zone classification. In conclusion, the impact of log P and pK(a) on hERG inhibition was clarified relatively and quantitatively. The quantitative risk assessment established based on both parameters, was considered to be a practical and useful tool in avoiding hERG inhibition and in the rational drug design for drug discovery, especially in lead optimization. Moreover, we also carried out a trend analysis using a different derivative and demonstrated that both parameters were equally significant for hERG inhibition.
authors: Drug Metabolism & Pharmacokinetics Research Laboratories, Daiichi Sankyo Co., Ltd., Japan.. kawai.yukinori.f5@daiichisankyo.co.jp
authors: Yukinori
authors: Y
authors: Kawai
authors: Shinsaku
authors: S
authors: Tsukamoto
authors: Junko
authors: J
authors: Ito
authors: Katsuya
authors: K
authors: Akimoto
authors: Masayuki
authors: M
authors: Takahashi
mesh_terms: D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology; D000935:Antifungal Agents / Q000737:chemistry / Q000494:pharmacology; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D006863:Hydrogen-Ion Concentration; D057927:Hydrophobic and Hydrophilic Interactions; D008133:Long QT Syndrome / Q000139:chemically induced; D015363:Quinolones / Q000737:chemistry / Q000494:pharmacology; D018570:Risk Assessment
chemical_list: D000900:Anti-Bacterial Agents; D000935:Antifungal Agents; D051638:Ether-A-Go-Go Potassium Channels; D015363:Quinolones