Pharmacological evaluation of a novel corticotropin-releasing factor 1 receptor antagonist T-3047928 in stress-induced animal models in a comparison with alosetron
Yasuo Itomi
Inflammation DDU, Pharmacological Research Division, Takeda Pharmaceutical Company Limited, Kanagawa, Japan
Search for more papers by this authorTakahiro Tanaka
Inflammation DDU, Pharmacological Research Division, Takeda Pharmaceutical Company Limited, Kanagawa, Japan
Search for more papers by this authorKozo Matsushita
Inflammation DDU, Pharmacological Research Division, Takeda Pharmaceutical Company Limited, Kanagawa, Japan
Search for more papers by this authorToru Kawamura
Inflammation DDU, Pharmacological Research Division, Takeda Pharmaceutical Company Limited, Kanagawa, Japan
Search for more papers by this authorTakuto Kojima
Inflammation DDU, Pharmacological Research Division, Takeda Pharmaceutical Company Limited, Kanagawa, Japan
Search for more papers by this authorKazuyoshi Aso
Inflammation DDU, Pharmacological Research Division, Takeda Pharmaceutical Company Limited, Kanagawa, Japan
Search for more papers by this authorShiho Matsumoto-Okano
Inflammation DDU, Pharmacological Research Division, Takeda Pharmaceutical Company Limited, Kanagawa, Japan
Search for more papers by this authorCorresponding Author
Yasuhiro Tsukimi
Inflammation DDU, Pharmacological Research Division, Takeda Pharmaceutical Company Limited, Kanagawa, Japan
Correspondence
Yasuhiro Tsukimi, Research Division, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
Email: [email protected]
Search for more papers by this authorYasuo Itomi
Inflammation DDU, Pharmacological Research Division, Takeda Pharmaceutical Company Limited, Kanagawa, Japan
Search for more papers by this authorTakahiro Tanaka
Inflammation DDU, Pharmacological Research Division, Takeda Pharmaceutical Company Limited, Kanagawa, Japan
Search for more papers by this authorKozo Matsushita
Inflammation DDU, Pharmacological Research Division, Takeda Pharmaceutical Company Limited, Kanagawa, Japan
Search for more papers by this authorToru Kawamura
Inflammation DDU, Pharmacological Research Division, Takeda Pharmaceutical Company Limited, Kanagawa, Japan
Search for more papers by this authorTakuto Kojima
Inflammation DDU, Pharmacological Research Division, Takeda Pharmaceutical Company Limited, Kanagawa, Japan
Search for more papers by this authorKazuyoshi Aso
Inflammation DDU, Pharmacological Research Division, Takeda Pharmaceutical Company Limited, Kanagawa, Japan
Search for more papers by this authorShiho Matsumoto-Okano
Inflammation DDU, Pharmacological Research Division, Takeda Pharmaceutical Company Limited, Kanagawa, Japan
Search for more papers by this authorCorresponding Author
Yasuhiro Tsukimi
Inflammation DDU, Pharmacological Research Division, Takeda Pharmaceutical Company Limited, Kanagawa, Japan
Correspondence
Yasuhiro Tsukimi, Research Division, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
Email: [email protected]
Search for more papers by this author[The copyright line for this article was changed on 24 July 2020 after original online publication.]
Abstract
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.
CONFLICT OF INTEREST
The authors have no competing interests.
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