ccx282-b and Colitis--Ulcerative

Inflammatory bowel disease (IBD) is a chronic, debilitating condition with a significant impact on quality of life. In spite of recent advances with antibody therapies, there remains a significant unmet medical need in IBD. Ongoing research and development efforts aim to identify new therapies that will increase remission rates beyond those achieved with current standard-of-care, while maintaining a high safety margin. This review will provide an overview of the small-molecule agents that are being explored in this regard.

Topics: Animals; Colitis, Ulcerative; Crohn Disease; Gastrointestinal Agents; Humans; Protein Kinase Inhibitors; Signal Transduction

The increased understanding of the molecular mechanisms that are responsible for inflammatory bowel disease (IBD) has led to a wide range of potential therapeutic targets for this condition. Physicians treating individuals with Crohn's disease and ulcerative colitis have a growing armamentarium of options to choose from in managing these patients. This article aims to summarize the relevant literature in the area of emerging therapy in IBD.. The widespread use of antitumor necrosis factor medications brought a landmark change in the treatment of IBD. More recently, several drugs have been shown to provide benefit in IBD in phase III studies by blocking other antiinflammatory pathways. The most likely new medications that will be available include vedolizumab for ulcerative colitis and ustekinumab for Crohn's disease, which target cellular adhesion and inflammatory cell signaling, respectively. Other promising drugs focus on blockade of Janus kinase, inhibition of various chemokines, and biologic therapy such as hematopoietic stem cell transplants and mesenchymal cell infusions.. The growing understanding of the pathogenesis of IBD has led to new molecular targets for therapy. Over the next decade, the number of treatments available will grow, targeting cellular adhesion, protein regulation, inflammatory signal pathways, and immune tolerance.

Topics: Anti-Inflammatory Agents; Antibodies, Monoclonal, Humanized; Colitis, Ulcerative; Crohn Disease; Hematopoietic Stem Cell Transplantation; Humans; Molecular Targeted Therapy; Natalizumab; Signal Transduction; Sulfonamides; Treatment Outcome; Ustekinumab

Irritable bowel diseases (IBD) such as Crohn's disease (CD) and ulcerative colitis (UC) are serious chronic diseases affecting millions of patients worldwide. Studies of human chemokine biology has suggested C-C chemokine receptor 9 (CCR9) may be a key mediator of pro-inflammatory signaling. Discovery of agents that inhibit CCR9 may lead to new therapies for CD and UC patients. Herein we describe the evolution of a high content screening hit (1) into potent inhibitors of CCR9, such as azaindole 12.

Topics: Colitis, Ulcerative; Crohn Disease; Dose-Response Relationship, Drug; Drug Discovery; Humans; Indoles; Molecular Structure; Receptors, CCR; Structure-Activity Relationship

While it has long been established that the chemokine receptor CCR9 and its ligand CCL25 are essential for the movement of leukocytes into the small intestine and the development of small-intestinal inflammation, the role of this chemokine-receptor pair in colonic inflammation is not clear. Toward this end, we compared colonic CCL25 protein levels in healthy individuals to those in patients with ulcerative colitis. In addition, we determined the effect of CCR9 pharmacological inhibition in the mdr1a(-/-) mouse model of ulcerative colitis. Colon samples from patients with ulcerative colitis had significantly higher levels of CCL25 protein compared to healthy controls, a finding mirrored in the mdr1a(-/-) mice. In the mdr1a(-/-) mice, CCR9 antagonists significantly decreased the extent of wasting and colonic remodeling and reduced the levels of inflammatory cytokines in the colon. These findings indicate that the CCR9:CCL25 pair plays a causative role in ulcerative colitis and suggest that CCR9 antagonists will provide a therapeutic benefit in patients with colonic inflammation.

Topics: Animals; ATP Binding Cassette Transporter, Subfamily B; Chemokines, CC; Colitis, Ulcerative; Female; Humans; In Vitro Techniques; Mice; Mice, Knockout; Receptors, CCR; Sulfonamides