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

  • Bioorg Med Chem Lett. 2013 Dec 15;23(24):6890-6. doi: 10.1016/j.bmcl.2013.09.090.
David M Wilson  1 ,  James Apps ,  Nicholas Bailey ,  Mark J Bamford ,  Isabel J Beresford ,  Kim Brackenborough ,  Michael A Briggs ,  Stephen Brough ,  Andrew R Calver ,  Barry Crook ,  Rebecca K Davis ,  Robert P Davis ,  Susannah Davis ,  David K Dean ,  Leanne Harris ,  Teresa Heslop ,  Vicky Holland ,  Phillip Jeffrey ,  Terrance A Panchal ,  Christopher A Parr ,  Nigel Quashie ,  Joanne Schogger ,  Sanjeet S Sehmi ,  Tania O Stean ,  Jon G A Steadman ,  Brenda Trail ,  Jeffrey Wald ,  Angela Worby ,  Andrew K Takle ,  Jason Witherington ,  Andrew D Medhurst
Affiliations
  • 1. GlaxoSmithKline R&D, Neurology Centre of Excellence for Drug Discovery, Harlow, Essex CM19 5AW, United Kingdom. Electronic address: [email protected].
PMID: 24269482 DOI: 10.1016/j.bmcl.2013.09.090
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.

Keywords
Clinical candidate; GPCR; H(3) receptor; Histamine; Lead optimisation; Neurotransmitters; Receptor antagonists.
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