title: Diaminopyrimidines, diaminopyridines and diaminopyridazines as histamine H4 receptor modulators.
abstract: Previously disclosed H4 receptor modulators, the triamino substituted pyridines and pyrimidines, contain a free primary amino (-NH2) group. In this Letter we demonstrate that an exocyclic amine (NH2) is not needed to maintain affinity, and also show a significant divergence in the SAR of the pendant diamine component. These des-NH2 azacycles also show a distinct functional spectrum, that appears to be influenced by the diamine component; in the case of the 1,3-amino pyrimidines, the preferred diamine is the amino pyrrolidine instead of the more common piperazines. Finally, we introduce 3,5-diamino pyridazines as novel histamine H4 antagonists.
authors.affiliation: Janssen Pharmaceutical Research & Development, LLC, 3210 Merryfield Row, San Diego, CA 92121, United States. Electronic address: bsavall@its.jnj.com.
authors.forename: Brad M
authors.initials: BM
authors.lastname: Savall
authors.affiliation: Janssen Pharmaceutical Research & Development, LLC, 3210 Merryfield Row, San Diego, CA 92121, United States.
authors.forename: Steven P
authors.initials: SP
authors.lastname: Meduna
authors.affiliation: Janssen Pharmaceutical Research & Development, LLC, 3210 Merryfield Row, San Diego, CA 92121, United States.
authors.forename: Kevin
authors.initials: K
authors.lastname: Tays
authors.affiliation: Janssen Pharmaceutical Research & Development, LLC, 3210 Merryfield Row, San Diego, CA 92121, United States.
authors.forename: Hui
authors.initials: H
authors.lastname: Cai
authors.affiliation: Janssen Pharmaceutical Research & Development, LLC, 3210 Merryfield Row, San Diego, CA 92121, United States.
authors.forename: Robin L
authors.initials: RL
authors.lastname: Thurmond
authors.affiliation: Janssen Pharmaceutical Research & Development, LLC, 3210 Merryfield Row, San Diego, CA 92121, United States.
authors.forename: Patricia
authors.initials: P
authors.lastname: McGovern
authors.affiliation: Janssen Pharmaceutical Research & Development, LLC, 3210 Merryfield Row, San Diego, CA 92121, United States.
authors.forename: Michael
authors.initials: M
authors.lastname: Gaul
authors.affiliation: Janssen Pharmaceutical Research & Development, LLC, 3210 Merryfield Row, San Diego, CA 92121, United States.
authors.forename: Bao-Ping
authors.initials: BP
authors.lastname: Zhao
authors.affiliation: Janssen Pharmaceutical Research & Development, LLC, 3210 Merryfield Row, San Diego, CA 92121, United States.
authors.forename: James P
authors.initials: JP
authors.lastname: Edwards
mesh_terms: D006801:Humans; D011725:Pyridines / Q000737:chemistry / Q000494:pharmacology*; D043562:Receptors, G-Protein-Coupled / Q000187:drug effects*; D011968:Receptors, Histamine / Q000187:drug effects*; D000074040:Receptors, Histamine H4
chemical_list: C418607:HRH4 protein, human; D011725:Pyridines; D043562:Receptors, G-Protein-Coupled; D011968:Receptors, Histamine; D000074040:Receptors, Histamine H4
keywords: Antagonists; Histamine H(4); Pyridazine; Pyridine; Pyrimidine