title: Challenges of drug discovery in novel target space. The discovery and evaluation of PF-3893787: a novel histamine H4 receptor antagonist.
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.
authors.affiliation: Worldwide Medicinal Chemistry, Pfizer Worldwide Research and Development, Sandwich, Kent CT13 9NJ, UK. Charlie.Mowbray@googlemail.com
authors.forename: Charles E
authors.initials: CE
authors.lastname: Mowbray
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Bell
authors.forename: Nicholas P
authors.initials: NP
authors.lastname: Clarke
authors.forename: Michelle
authors.initials: M
authors.lastname: Collins
authors.forename: Rhys M
authors.initials: RM
authors.lastname: Jones
authors.forename: Charlotte A L
authors.initials: CA
authors.lastname: Lane
authors.forename: Wai L
authors.initials: WL
authors.lastname: Liu
authors.forename: Sandra D
authors.initials: SD
authors.lastname: Newman
authors.forename: Michael
authors.initials: M
authors.lastname: Paradowski
authors.forename: Emanuel J
authors.initials: EJ
authors.lastname: Schenck
authors.forename: Mathew D
authors.initials: MD
authors.lastname: Selby
authors.forename: Nigel A
authors.initials: NA
authors.lastname: Swain
authors.forename: David H
authors.initials: DH
authors.lastname: Williams
mesh_terms: D000818:Animals; D055808:Drug Discovery; D004353:Drug Evaluation, Preclinical; D006633:Histamine Antagonists / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D011743:Pyrimidines / Q000737:chemistry* / Q000494:pharmacology*; D011759:Pyrrolidines / Q000737:chemistry* / Q000494:pharmacology*; D051381:Rats; D043562:Receptors, G-Protein-Coupled / Q000187:drug effects*; D011968:Receptors, Histamine / Q000187:drug effects*; D000074040:Receptors, Histamine H4
chemical_list: C418607:HRH4 protein, human; D006633:Histamine Antagonists; D011743:Pyrimidines; D011759:Pyrrolidines; D043562:Receptors, G-Protein-Coupled; D011968:Receptors, Histamine; D000074040:Receptors, Histamine H4; C569544:PF-3893787