Identification of clinical candidates from the benzazepine class of histamine H3 receptor antagonists.

Autor: Wilson DM; GlaxoSmithKline R&D, Neurology Centre of Excellence for Drug Discovery, Harlow, Essex CM19 5AW, United Kingdom. Electronic address: David.M.Wilson@astrazeneca.com., Apps J, Bailey N, Bamford MJ, Beresford IJ, Brackenborough K, Briggs MA, Brough S, Calver AR, Crook B, Davis RK, Davis RP, Davis S, Dean DK, Harris L, Heslop T, Holland V, Jeffrey P, Panchal TA, Parr CA, Quashie N, Schogger J, Sehmi SS, Stean TO, Steadman JG, Trail B, Wald J, Worby A, Takle AK, Witherington J, Medhurst AD
Jazyk: angličtina
Zdroj: Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2013 Dec 15; Vol. 23 (24), pp. 6890-6. Date of Electronic Publication: 2013 Oct 05.
DOI: 10.1016/j.bmcl.2013.09.090
Abstrakt: This Letter describes the discovery of GSK189254 and GSK239512 that were progressed as clinical candidates to explore the potential of H3 receptor antagonists as novel therapies for the treatment of Alzheimer's disease and other dementias. By carefully controlling the physicochemical properties of the benzazepine series and through the implementation of an aggressive and innovative screening strategy that employed high throughput in vivo assays to efficiently triage compounds, the medicinal chemistry effort was able to rapidly progress the benzazepine class of H3 antagonists through to the identification of clinical candidates with robust in vivo efficacy and excellent developability properties.
(Copyright © 2013 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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