Structure-activity studies on a series of a 2-aminopyrimidine-containing histamine H4 receptor ligands.
A series of 2-aminopyrimidines was synthesized as ligands of the histamine H4 receptor (H4R). Working in part from a pyrimidine hit that was identified in an HTS campaign, SAR studies were carried out to optimize the potency, which led to compound 3, 4- tert-butyl-6-(4-methylpiperazin-1-yl)pyrimidin-2-ylamine. We further studied this compound by systematically modifying the core pyrimidine moiety, the methylpiperazine at position 4, the NH2 at position 2, and positions 5 and 6 of the pyrimidine ring. The pyrimidine 6 position benefited the most from this optimization, especially in analogs in which the 6- tert-butyl was replaced with aromatic and secondary amine moieties. The highlight of the optimization campaign was compound 4, 4-[2-amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]benzonitrile, which was potent in vitro and was active as an anti-inflammatory agent in an animal model and had antinociceptive activity in a pain model, which supports the potential of H 4R antagonists in pain.
Altenbach
Robert J
RJ
Neuroscience Research, Global Pharmaceutical Research and Development, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, Illinois 60064-6100, USA. Robert.j.altenbach@abbott.com
Adair
Ronald M
RM
Bettencourt
Brian M
BM
Black
Lawrence A
LA
Fix-Stenzel
Shannon R
SR
Gopalakrishnan
Sujatha M
SM
Hsieh
Gin C
GC
Liu
Huaqing
H
Marsh
Kennan C
KC
McPherson
Michael J
MJ
Milicic
Ivan
I
Miller
Thomas R
TR
Vortherms
Timothy A
TA
Warrior
Usha
U
Wetter
Jill M
JM
Wishart
Neil
N
Witte
David G
DG
Honore
Prisca
P
Esbenshade
Timothy A
TA
Hancock
Arthur A
AA
Brioni
Jorge D
JD
Cowart
Marlon D
MD
D000818:Animals; D015415:Biomarkers; D006633:Histamine Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D006965:Hyperplasia / Q000139:chemically induced / Q000517:prevention & control; D008024:Ligands; D008124:Locomotion / Q000187:drug effects; D051379:Mice; D015394:Molecular Structure; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D011968:Receptors, Histamine / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
D015415:Biomarkers; D006633:Histamine Antagonists; D008024:Ligands; D011743:Pyrimidines; D011968:Receptors, Histamine; C012180:2-aminopyrimidine