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MOREE, Wilna J; JOVIC, Florence; HERNANDEZ, Lisa M; O'BRIEN, Zhihong; JIANYUN WEN; HUA WANG; HOARE, Samuel R. J; PETROSKI, Robert E; SACAAN, Aida; MADAN, Ajay; CROWE, Paul D; BEATON, Graham; COON, Timothy; JINGHUA YU; LI, Bin-Feng; TUCCI, Fabio C; MARINKOVIC, Dragan; GROSS, Raymond S; MALANY, Siobhan; BRADBURY, Margaret J
Bioorganic & medicinal chemistry letters, 04/2010, Letnik: 20, Številka: 7Journal Article
SAR of lead benzothiophene H(1)-antihistamine 2 was explored to identify backup candidates with suitable pharmacokinetic profiles for an insomnia program. Several potent and selective H(1)-antihistamines with a range of projected half-lives in humans were identified. Compound 16d had a suitable human half-life as demonstrated in a human microdose study, but variability in pharmacokinetic profile, attributed to metabolic clearance, prevented further development of this compound. Compound 28b demonstrated lower predicted clearance in preclinical studies, and may represent a more suitable backup compound.
