In order to create a new
drug for the treatment of
respiratory diseases, such as
asthma and
chronic bronchitis, having a novel therapeutic mechanism, we have been trying to develop new compounds with neurokinin (NK)-receptor antagonistic effects. We used [3H]-
substance P binding to guinea pig lung membrane for the first screening system and successfully discovered
FK224 from a fermentation product and
FK888 from chemical design studies using an octapeptide antagonist (D-Pro4,D-Trp7,9,10) SP4-11 as the parent compound.
FK224 and
FK888 showed different selectivities against the NK-receptor subtypes (NK1, NK2, NK3);
FK888 was a highly potent NK1-selective antagonist, and
FK224 was a NK1 + NK2 dual receptor antagonist. Neither compound had any activity on the NK3 receptor. In the in vivo experiments,
FK224 and
FK888 significantly inhibited the constriction and plasma extravasation in the airway induced by agonist injection. These compounds also showed inhibitory effects on the airway response induced by
capsaicin and antidromic stimulation of vagus nerves. Furthermore,
FK224 and
FK888 were effective on the mucus secretion in the airway and the
cough reflex induced by
citric acid challenge. There were some differences in the effects of
FK224 and
FK888 in the in vivo experiments, and it was suggested that the NK1 receptor and NK2 receptor were mainly involved in
neurogenic inflammation and airway constriction, respectively.
FK224 and
FK888 are now undergoing clinical studies to test the effectiveness of a NK antagonist in human
respiratory diseases.