title: The effect of pK(a) on pyrimidine/pyridine-derived histamine H4 ligands.
abstract: During the course of our efforts toward the discovery of human histamine H4 antagonists from a series of 2-aminiopyrimidines, it was noted that a 6-trifluoromethyl group dramatically reduced affinity of the series toward the histamine H4 receptor. This observation was further investigated by synthesizing a series of ligands that varied in pKa of the pyrimidine derived H4 ligands by over five orders of magnitude and the effect on histamine H4 affinity. This trend was then extended to the discovery of C-linked piperidinyl-2-amino pyridines as histamine H4 receptor antagonists.
authors.affiliation: Janssen Pharmaceutical Research & Development, LLC, 3210 Merryfield Row, San Diego, CA 92121, United States.
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: Jennifer
authors.initials: J
authors.lastname: Venable
authors.affiliation: Janssen Pharmaceutical Research & Development, LLC, 3210 Merryfield Row, San Diego, CA 92121, United States.
authors.forename: Jianmei
authors.initials: J
authors.lastname: Wei
authors.affiliation: Janssen Pharmaceutical Research & Development, LLC, 3210 Merryfield Row, San Diego, CA 92121, United States.
authors.forename: Russell C
authors.initials: RC
authors.lastname: Smith
authors.affiliation: Janssen Pharmaceutical Research & Development, LLC, 3210 Merryfield Row, San Diego, CA 92121, United States.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Hack
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: James P
authors.initials: JP
authors.lastname: Edwards
mesh_terms: D006633:Histamine Antagonists / Q000493:pharmacokinetics* / Q000627:therapeutic use; D006801:Humans; D008024:Ligands; D015394:Molecular Structure; D011725:Pyridines / Q000737:chemistry*; D011743:Pyrimidines / Q000737:chemistry*; 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; D008024:Ligands; D011725:Pyridines; D011743:Pyrimidines; D043562:Receptors, G-Protein-Coupled; D011968:Receptors, Histamine; D000074040:Receptors, Histamine H4; C030986:pyrimidine; C023666:pyridine
keywords: Aminopyrimidine; H(4); Histamine H(4); Pyridine; Pyrimidine; pK(a)