Abstract. TAK-480, 4-(difluoromethoxy)-N-((1R,2S)-2-(((3aR,4R,9bR)-4-(methoxymethyl)-2, 3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinolin-1-yl)carbonyl)cyclohexyl)benzamide, is a novel tachykinin NK 2 -receptor antagonist. In this study, we investigated its antagonistic activity and efficacy in animal models of visceral hypersensitivity and stimulated bowel function which have been implicated to underlie the symptoms in irritable bowel syndrome (IBS). TAK-480 showed potent binding affinity for human NK 2 receptors with a marked species difference and a 10,000-fold selectivity versus NK 1 and NK 3 receptors. TAK-480 dose-dependently antagonized colonic contractions induced by administration of the NK 2 receptor-selective agonist beta-Ala 8 -NKA(4-10) (βA-NKA) in anesthetized rabbits. In a rabbit model of intracolonic zymosan-induced visceral hypersensitivity, TAK-480 markedly inhibited the visceromotor response to colorectal distension, in contrast to the moderate inhibition by the serotonin 5-HT 3 -receptor antagonist alosetron. In addition, TAK-480 suppressed ricinoleic acid-induced defecation without affecting spontaneous defecation in guinea pigs, whereas alosetron suppressed both. Furthermore, TAK-480 inhibited smooth muscle contractions produced by natural tachykinins (substance P, neurokinin A, and neurokinin B) as well as βA-NKA in an isolated human colon. In conclusion, the novel NK 2 -receptor antagonist TAK-480 improved visceral hypersensitivity and accelerated defecation without causing constipation in experimental animals. Furthermore, the potent functional blockade of NK 2 receptors in human colon might suggest the potential effectiveness of TAK-480 in IBS patients.

Abstract. We attempted to establish and validate an in vivo pharmacodynamic (PD) rabbit model to screen tachykinin NK 2 receptor (NK 2 -R) antagonists using pharmacological and pharmacokinetic (PK)/PD analyses. Under urethane anesthesia, changes in intracolonic pressure associated with intravenous (i.v.) administration of a selective NK 2 -R agonist, βAla 8 -neurokinin A(4-10) (βA-NKA), was monitored as a PD marker. The analgesic effects of NK 2 -R antagonists were evaluated by monitoring visceromotor response (VMR) to colorectal distension in a rabbit model of visceral hypersensitivity induced by intracolonic treatment of acetic acid. Intravenous administration of βA-NKA induced transient colonic contractions dose-dependently, which were inhibited by the selective NK 2 -R antagonists in dose-and/or plasma concentration-dependent manners. The correlation between PD inhibition and plasma concentration normalized with the corresponding in vitro binding affinity was relatively high (r 2 = 0.61). Furthermore, the minimum effective doses on the VMR and ID 50 values calculated in the PD model were highly correlated (r 2 = 0.74). In conclusion, we newly established and validated a rabbit model of agonist-induced colonic contractions as a screening tool for NK 2 -R antagonists. In a drug discovery process, this PD model could enhance the therapeutic candidate selection for irritable bowel syndrome, pharmacologically connecting in vitro affinity for NK 2 -R with in vivo therapeutic efficacy.

Background:The major symptoms of irritable bowel syndrome (IBS) are changes in bowel habits and abdominal pain. Psychological stress is the major pathophysiological components of IBS. Corticotropin-releasing factor (CRF) is a well-known integrator in response to psychological stress. In this study, a novel CRF1 receptor antagonist T-3047928 was evaluated in stress-induced IBS models of rats to explore its potency for IBS. Methods: Plasma adrenocorticotropic hormone (ACTH) levels after intravenous oCRH challenge were measured as a pharmacodynamic marker. Efficacies of oral T-3047928 were compared with oral alosetron, a 5-HT3 antagonist, on conditioning fear stress (CFS)-induced defecation, restraint stress (RS)-induced acute visceral pain, specific alteration of rhythm in temperature (SART) stress-induced chronic visceral pain, and normal defecation. Results: T-3047928 (1-10 mg/kg, p.o.) demonstrated a dose-dependent inhibition on oCRH-induced ACTH secretion. In disease models, T-3047928 suppressed fecal pellet output induced by CFS and improved both acute and chronic visceral hypersensitivity induced by RS and SART stress, respectively. Alosetron was also efficacious in stress-induced defecation and visceral pain models at 1 and 10 mg/kg, respectively.Alosetron, however, also suppressed normal defecation at lower those. On the other hand, T-3047928 did not change normal defecation even at higher dose than those in disease models. Conclusion:T-3047928 is an orally active CRF1 antagonist that demonstrated potent inhibitory effects in stress-associated IBS models with no effect on normal defecation. Therefore, it is suggested that T-3047928 may have a potency as a novel option for IBS-D therapy with minimal constipation risk. K E Y W O R D SAlosetron, CRF1 receptor antagonist, defecation, irritable bowel syndrome (IBS), stress, T-3047928, visceral pain

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