title: Discovery of a series of potent and selective human H4 antagonists using ligand efficiency and libraries to explore structure-activity relationship (SAR).
abstract: We describe the identification of a potent, selective lead series that shows antagonism against the human histamine H4 receptor from thirteen actives identified in an HTS as part of a hit to lead program. By focusing on ligand efficiency and concurrently using a diversity based approach, compounds based around 2,4-diaminopyrimidine were identified with compound 25 being quickly shown to be a good lead. It also had the highest ligand efficiency in the series.
authors.affiliation: Pfizer Worldwide Research and Development, Sandwich Laboratories, Ramsgate Road, Sandwich CT13 9NJ, UK. abid.masood@pfizer.com
authors.forename: M Abid
authors.initials: MA
authors.lastname: Masood
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Selby
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Bell
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Mansfield
authors.forename: Mark
authors.initials: M
authors.lastname: Gardner
authors.forename: Graham F
authors.initials: GF
authors.lastname: Smith
authors.forename: Charlotte
authors.initials: C
authors.lastname: Lane
authors.forename: Helen
authors.initials: H
authors.lastname: Kenyon-Edwards
authors.forename: Rachel
authors.initials: R
authors.lastname: Osborne
authors.forename: Rhys M
authors.initials: RM
authors.lastname: Jones
authors.forename: Wai L
authors.initials: WL
authors.lastname: Liu
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Brown
authors.forename: Nicholas
authors.initials: N
authors.lastname: Clarke
authors.forename: Francesca
authors.initials: F
authors.lastname: Perrucio
authors.forename: Charles E
authors.initials: CE
authors.lastname: Mowbray
mesh_terms: D006633:Histamine Antagonists / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D008024:Ligands; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors*; D011968:Receptors, Histamine; D000074040:Receptors, Histamine H4; D054852:Small Molecule Libraries; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: C418607:HRH4 protein, human; D006633:Histamine Antagonists; D008024:Ligands; D043562:Receptors, G-Protein-Coupled; D011968:Receptors, Histamine; D000074040:Receptors, Histamine H4; D054852:Small Molecule Libraries