Identification of a novel selective H1-antihistamine with optimized pharmacokinetic properties for clinical evaluation in the treatment of insomnia

✍ Scribed by Wilna J. Moree; Bin-Feng Li; Said Zamani-Kord; Jinghua Yu; Timothy Coon; Charles Huang; Dragan Marinkovic; Fabio C. Tucci; Siobhan Malany; Margaret J. Bradbury; Lisa M. Hernandez; Jianyun Wen; Hua Wang; Samuel R.J. Hoare; Robert E. Petroski; Kayvon Jalali; Chun Yang; Aida Sacaan; Ajay Madan; Paul D. Crowe; Graham Beaton

• Publisher: Elsevier Science
• Year: 2010
• Tongue: English
• Weight: 688 KB
• Volume: 20
• Category: Article
• ISSN: 0960-894X
• DOI: 10.1016/j.bmcl.2010.07.117

✦ Synopsis

Analogs of the known H(1)-antihistamine R-dimethindene with suitable selectivity for key GPCRs, P450 enzymes and hERG channel were assessed for metabolism profile and in vivo properties. Several analogs were determined to exhibit diverse metabolism. One of these compounds, 10a, showed equivalent efficacy in a rat EEG/EMG model to a previously identified clinical candidate and a potentially superior pharmacokinetic profile as determined from a human microdose study.