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

Autor:	Sam R. J. Hoare, Graham Beaton, Bin-Feng Li, Paul D. Crowe, Said Zamani-Kord, Lisa M. Hernández, Wilna J. Moree, Charles Q. Huang, Jinghua Yu, Hua Wang, Siobhan Malany, Fabio C. Tucci, Chun Yang, Ajay Madan, Aida Sacaan, Robert E. Petroski, Jianyun Wen, Coon Timothy Richard, Margaret J. Bradbury, Kayvon Jalali, Dragan Marinkovic
Rok vydání:	2010
Předmět:	CYP2D6 Clinical Biochemistry hERG Pharmaceutical Science Pharmacology Biochemistry Structure-Activity Relationship MicroDose Pharmacokinetics In vivo Sleep Initiation and Maintenance Disorders Drug Discovery Structure–activity relationship Animals Dimethindene Humans Receptors Histamine H1 Molecular Biology Unspecific monooxygenase biology Chemistry Organic Chemistry Antagonist Electroencephalography Rats Pyridazines Cytochrome P-450 CYP2D6 Indenes Models Animal biology.protein Histamine H1 Antagonists Microsomes Liver Molecular Medicine
Zdroj:	Bioorganicmedicinal chemistry letters. 20(19)
ISSN:	1464-3405
Popis:	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.
Databáze:	OpenAIRE
Externí odkaz:	https://explore.openaire.eu/search/publication?articleId=doi_dedup___::27771b1fadd5556d09bba470020874b2 https://pubmed.ncbi.nlm.nih.gov/20800486 Zobrazit plný text záznamu Full Text from ScienceDirect