Structural determinants for histamine H(1) affinity, hERG affinity and QTc prolongation in a series of terfenadine analogs.
In the late 1980's reports linking the non-sedating antihistamines terfenadine and astemizole with torsades de pointes, a form of ventricular tachyarrhythmia that can degenerate into ventricular fibrillation and sudden death, appeared in the clinical literature. A substantial body of evidence demonstrates that the arrhythmogenic effect of these cardiotoxic antihistamines, as well as a number of structurally related compounds, results from prolongation of the QT interval due to suppression of specific delayed rectifier ventricular K+ currents via blockade of the hERG-IKr channel. In order to better understand the structural requirements for hERG and H(1) binding for terfenadine, a series of analogs of terfenadine has been prepared and studied in both in vitro and in vivo hERG and H(1) assays.
Aslanian
Robert
R
The Schering Plough Research Institute, 2015 Galloping Hill Rd., Kenilworth, NJ 07033, USA. robert.aslanian@spcorp.com
Piwinski
John J
JJ
Zhu
Xiaohong
X
Priestley
Tony
T
Sorota
Steve
S
Du
Xiao-Yi
XY
Zhang
Xue-Song
XS
McLeod
Robbie L
RL
West
Robert E
RE
Williams
Shirley M
SM
Hey
John A
JA
D000818:Animals; D004562:Electrocardiography; D006168:Guinea Pigs; D039563:Histamine H1 Antagonists, Non-Sedating / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D011485:Protein Binding; D011969:Receptors, Histamine H1 / Q000378:metabolism*; D013329:Structure-Activity Relationship; D016593:Terfenadine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D015534:Trans-Activators / Q000378:metabolism*; D000071230:Transcriptional Regulator ERG
C072312:ERG protein, human; D039563:Histamine H1 Antagonists, Non-Sedating; D011969:Receptors, Histamine H1; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG; D016593:Terfenadine