ABSTRACT
This study evaluated the in vitro and in vivo pharmacological properties of TD-8954, a potent and selective 5-HT(4) receptor agonist. TD-8954 had high affinity (pK(i) = 9.4) for human recombinant 5-HT(4(c)) (h5-HT(4(c))) receptors, and selectivity (>2,000-fold) over all other 5-hydroxytryptamine (5-HT) receptors and non-5-HT receptors, ion channels, enzymes and transporters tested (n = 78). TD-8954 produced an elevation of cAMP in HEK-293 cells expressing the h5-HT(4(c)) receptor (pEC(50) = 9.3), and contracted the guinea pig colonic longitudinal muscle/myenteric plexus preparation (pEC(50) = 8.6). TD-8954 had moderate intrinsic activity in the in vitro assays. In conscious guinea pigs, subcutaneous administration of TD-8954 (0.03-3 mg/kg) increased the colonic transit of carmine red dye, reducing the time taken for its excretion. Following intraduodenal dosing to anesthetized rats, TD-8954 (0.03-10 mg/kg) evoked a dose-dependent relaxation of the esophagus. Following oral administration to conscious dogs, TD-8954 (10 and 30 µg/kg) produced an increase in contractility of the antrum, duodenum, and jejunum. In a single ascending oral dose study in healthy human subjects, TD-8954 (0.1-20 mg) increased bowel movement frequency and reduced the time to first stool. It is concluded that TD-8954 is a potent and selective 5-HT(4) receptor agonist in vitro, with robust in vivo stimulatory activity in the gastrointestinal (GI) tract of guinea pigs, rats, dogs, and humans. TD-8954 may have clinical utility in patients with disorders of reduced GI motility.
ABSTRACT
Therapeutic options for refractory colonic inflammation in patients with ulcerative colitis or Crohn's disease have recently been expanded with the introduction of biologic therapies. Intravenous corticosteroids and cyclosporine A remain the standard therapies for severe ulcerative colitis. Monoclonal antibodies directed at tumor necrosis factor-a have proven to be exceptionally efficacious in patients with severe or refractory Crohn's disease. Immunomodulatory therapy with azathioprine, 6-mercaptopurine, or methotrexate has demonstrated efficacy for maintenance of remission in patients with refractory ulcerative colitis or Crohn's disease. The use of experimental biologic agents may be considered for those patients who fail to respond to or remain dependent on corticosteroids. Surgical intervention still remains for patients with severe colitis who fail to respond to medical therapy or develop life-threatening complications such as perforation or toxic megacolon.