1. Identification of clinical candidates from the benzazepine class of histamine H3 receptor antagonists.
- Author
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Wilson DM, 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, and Medhurst AD
- Subjects
- Animals, Benzazepines pharmacokinetics, Dogs, Half-Life, Haplorhini, Histamine H3 Antagonists chemical synthesis, Histamine H3 Antagonists pharmacokinetics, Humans, Male, Microsomes, Liver metabolism, Niacinamide analogs & derivatives, Niacinamide chemistry, Niacinamide pharmacokinetics, Protein Binding, Rats, Rats, Sprague-Dawley, Receptors, Histamine H3 metabolism, Structure-Activity Relationship, Benzazepines chemistry, Histamine H3 Antagonists chemistry, Receptors, Histamine H3 chemistry
- Abstract
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.)
- Published
- 2013
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