1. Academic Validation
  2. Characteristics of the antihistamine effect of TAK-427, a novel imidazopyridazine derivative

Characteristics of the antihistamine effect of TAK-427, a novel imidazopyridazine derivative

  • Inflamm Res. 2003 May;52(5):206-14. doi: 10.1007/s000110300073.
S Fukuda 1 K Midoro M Yamasaki M Gyoten Y Kawano H Fukui Y Ashida H Nagaya
Affiliations

Affiliation

  • 1 Pharmaceutical Research Division, Takeda Chemical Industries, Ltd., 2-17-85, Juso-Honmachi, Yodogawa-ku, Osaka, 532-8686, Japan. Fukuda_Shigeru@takeda.co.jp
Abstract

Objective and design: The characteristics of the antihistamine effect of the new antiallergic compound TAK-427 were investigated.

Materials and 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.

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