Characteristics of the antihistamine effect of TAK-427, a novel imidazopyridazine derivative.
OBJECTIVE
The characteristics of the antihistamine effect of the new antiallergic compound TAK-427 were investigated.


METHODS
In vitro binding assay of [(3)H] pyrilamine was performed using recombinant human histamine H(1) receptors (rhH(1)R). In vivo studies were performed in male ICR mice or Hartley guinea pigs. Drugs were administered orally 1 h before examinations. Determinations were made of histamine-induced skin reaction, ex vivo measured radioligand binding to brain and lung H(1) receptors, pentobarbital-induced sleeping time, passive cutaneous anaphylaxis (PCA) reaction, and antigen-induced itch-scratch responses (ISRs).


RESULTS
TAK-427 inhibited ligand binding to rhH(1)R with an IC(50) value of 17.3 nmol/l. TAK-427 inhibited histamine-induced skin reactions in guinea pigs and mice with an ID(50) value of 0.884 and 0.450 mg/kg, p.o., respectively; significant inhibition associated with 10 mg/kg of TAK-427 was still observed 24 h after dosing in guinea pigs. TAK-427 showed as high selectivity for peripheral H(1) receptors as terfenadine and epinastine did, which was evaluated by ex vivo measured radioligand binding. Even at 300 mg/kg, TAK-427 did not affect pentobarbital-induced sleeping time in mice. TAK-427 significantly inhibited PCA in mice and guinea pigs, and also inhibited antigen-induced ISRs in guinea pigs.


CONCLUSIONS
These results suggest that TAK-427 may have a long-lasting antihistamine activity with minimum sedative side effect and suppress acute phase allergic reactions.
Fukuda
S
S
Pharmaceutical Research Division, Takeda Chemical Industries, Ltd., 2-17-85, Juso-Honmachi, Yodogawa-ku, Osaka, 532-8686, Japan. Fukuda_Shigeru@takeda.co.jp
Midoro
K
K
Yamasaki
M
M
Gyoten
M
M
Kawano
Y
Y
Fukui
H
H
Ashida
Y
Y
Nagaya
H
H
D000465:Algorithms; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001667:Binding, Competitive / Q000187:drug effects; D001921:Brain / Q000378:metabolism; D006168:Guinea Pigs; D006633:Histamine Antagonists; D006634:Histamine H1 Antagonists / Q000494:pharmacology; D006801:Humans; D006993:Hypnotics and Sedatives / Q000494:pharmacology; D007093:Imidazoles / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D010047:Ovalbumin / Q000276:immunology; D010323:Passive Cutaneous Anaphylaxis / Q000187:drug effects; D010424:Pentobarbital / Q000494:pharmacology; D011537:Pruritus / Q000517:prevention & control; D011724:Pyridazines / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D011869:Radioligand Assay; D011969:Receptors, Histamine H1 / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D012890:Sleep / Q000187:drug effects; D013997:Time Factors
C469683:2-(6-((3-(4-(diphenylmethoxy)piperidino)propyl)amino)imidazo(1,2-b)pyridazin-2-yl)-2-methylpropionic acid; D006633:Histamine Antagonists; D006634:Histamine H1 Antagonists; D006993:Hypnotics and Sedatives; D007093:Imidazoles; D011724:Pyridazines; D011969:Receptors, Histamine H1; D011994:Recombinant Proteins; D010047:Ovalbumin; D010424:Pentobarbital