Challenges of drug discovery in novel target space. The discovery and evaluation of PF-3893787: a novel histamine H4 receptor antagonist

  • Bioorg Med Chem Lett. 2011 Nov 1;21(21):6596-602. doi: 10.1016/j.bmcl.2011.07.125.
Charles E Mowbray  1 ,  Andrew S Bell ,  Nicholas P Clarke ,  Michelle Collins ,  Rhys M Jones ,  Charlotte A L Lane ,  Wai L Liu ,  Sandra D Newman ,  Michael Paradowski ,  Emanuel J Schenck ,  Mathew D Selby ,  Nigel A Swain ,  David H Williams
Affiliations
  • 1. Worldwide Medicinal Chemistry, Pfizer Worldwide Research and Development, Sandwich, Kent CT13 9NJ, UK. [email protected]
PMID: 21920751 DOI: 10.1016/j.bmcl.2011.07.125
Abstract

We describe the development of novel benzimidazoles as small molecule histamine H4 receptor (H4R) antagonists and their profiling in rat early toxicity studies. The discovery and optimisation of a second series of pyrimidine based antagonists is then described culminating in the identification of the clinical development candidate 13 (PF-3893787). The pre-clinical profile of 13 (PF-3893787) is presented including the development of a translatable biomarker. Our pragmatic approach to target selection, safety assessment, and testing for efficacy faced numerous challenges and we share a number of lessons which the team learned and which will assist us and Others in future drug discovery projects.

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