ccx282-b and Inflammatory-Bowel-Diseases

Inflammatory bowel disease (IBD) is a chronic and recurrent inflammatory disease in the gastrointestinal tract emerged as a public health challenge worldwide. IBD exhibits a relapsing and remitting course results in negative impacts on both physical and psychological health of IBD patients. Great efforts have been made during the past few years, but relatively limited drugs are currently available for the management of IBD. Clinically, there is a strong demand for new drugs for the treatment of IBD with better efficacy and lower side effects. This review focuses on the drug discovery process of the anti-IBD agents, aiming to introduce the general characteristics of IBD, as well as systematically summarize the recent advances in the discovery of small-molecule candidates and natural products with promising in vivo potential for the treatment of IBD.

Topics: Biological Products; Drug Discovery; Humans; Inflammatory Bowel Diseases; Molecular Structure; Small Molecule Libraries

The principal targets for anti-chemokine therapy in inflammatory bowel disease (IBD) have been the receptors CCR9 and CXCR3 and their respective ligands CCL25 and CXCL10. More recently CCR6 and its ligand CCL20 have also received attention, the expression of the latter in enterocytes being manipulated through Smad7 signalling. These pathways, selected based on their fundamental role in regulating mucosal immunity, have led to the development of several therapeutic candidates that have been tested in early phase clinical trials with variable clinical efficacy. In this article, we appraise the status of chemokine-directed therapy in IBD, review recent developments, and nominate future areas for therapeutic focus.

Topics: Animals; Antibodies, Monoclonal; Chemokine CCL20; Chemokine CXCL10; Chemokines; Chemokines, CC; Gastrointestinal Agents; Humans; Inflammatory Bowel Diseases; Molecular Targeted Therapy; Oligonucleotides; Receptors, CCR; Receptors, CCR6; Receptors, Chemokine; Receptors, CXCR3; Smad7 Protein; Sulfonamides

Lymphocyte homing antagonists represent promising therapeutic agents for the treatment of idiopathic inflammatory bowel disease (IBD). Several critical molecules involved in the recruitment of inflammatory cells in the intestine, including integrins and chemokine receptors, have been successfully targeted for the treatment of IBD. These agents have shown great promise for the induction and maintenance of remission for both Crohn disease and ulcerative colitis. This article discusses currently approved prototypic agents for the treatment of IBD (natalizumab, anti-α4 integrin; vedolizumab, anti-α4β7 integrin), and several other agents in the same class currently under development.

Topics: Animals; Antibodies, Monoclonal, Humanized; Cell Adhesion Molecules; Gastrointestinal Agents; Humans; Immunoglobulins; Inflammatory Bowel Diseases; Integrins; Intercellular Adhesion Molecule-1; Mucoproteins; Natalizumab; Phenylalanine; Phosphorothioate Oligonucleotides; Quinazolinones; Receptors, CCR; Sulfonamides

Chemokine receptor 9 (CCR9), a cell surface chemokine receptor which belongs to the G protein-coupled receptor, 7-trans-membrane superfamily, is expressed on lymphocytes in the circulation and is the key chemokine receptor that enables these cells to target the intestine. It has been proposed that CCR9 antagonism represents a means to prevent the aberrant immune response of inflammatory bowel disease in a localized and disease specific manner and one which is accessible to small molecule approaches. One possible reason why clinical studies with vercirnon, a prototype CCR9 antagonist, were not successful may be due to a relatively poor pharmacokinetic (PK) profile for the molecule. We wish to describe work aimed at producing new, orally active CCR9 antagonists based on the 1,3-dioxoisoindoline skeleton. This study led to a number of compounds that were potent in the nanomolar range and which, on optimization, resulted in several possible preclinical development candidates with excellent PK properties.

Topics: Administration, Oral; Animals; Biological Availability; Chemistry Techniques, Synthetic; Chemotaxis; Colitis; Disease Models, Animal; Humans; Inflammatory Bowel Diseases; Isoindoles; Male; Mice, Inbred C57BL; Receptors, CCR; Structure-Activity Relationship; Sulfonamides

Inflammatory bowel disease, including Crohn's disease and ulcerative colitis, affects millions of people worldwide. CCR9 has been shown to be a key chemokine receptor mediating the local inflammatory responses in the GI tract. The CCR9 inhibitor Vercirnon advanced to phase 3 clinical trials, but carries several liabilities which we sought to improve.

Topics: Animals; Chemistry Techniques, Synthetic; Drug Evaluation, Preclinical; Humans; Inflammatory Bowel Diseases; Inhibitory Concentration 50; Mice; Receptors, CCR; Structure-Activity Relationship; Sulfonamides

The chemokine system represents a diverse group of G protein-coupled receptors responsible for orchestrating cell recruitment under both homeostatic and inflammatory conditions. Chemokine receptor 9 (CCR9) is a chemokine receptor known to be central for migration of immune cells into the intestine. Its only ligand, CCL25, is expressed at the mucosal surface of the intestine and is known to be elevated in intestinal inflammation. To date, there are no reports of small-molecule antagonists targeting CCR9. We report, for the first time, the discovery of a small molecule, CCX282-B, which is an orally bioavailable, selective, and potent antagonist of human CCR9. CCX282-B inhibited CCR9-mediated Ca(2+) mobilization and chemotaxis on Molt-4 cells with IC(50) values of 5.4 and 3.4 nM, respectively. In the presence of 100% human serum, CCX282-B inhibited CCR9-mediated chemotaxis with an IC(50) of 33 nM, and the addition of α1-acid glycoprotein did not affect its potency. CCX282-B inhibited chemotaxis of primary CCR9-expressing cells to CCL25 with an IC(50) of 6.8 nM. CCX282-B was an equipotent inhibitor of CCL25-directed chemotaxis of both splice forms of CCR9 (CCR9A and CCR9B) with IC(50) values of 2.8 and 2.6 nM, respectively. CCX282-B also inhibited mouse and rat CCR9-mediated chemotaxis. Inhibition of CCR9 with CCX282-B results in normalization of Crohn's disease such as histopathology associated with the TNF(ΔARE) mice. Analysis of the plasma level of drug associated with this improvement provides an understanding of the pharmacokinetic/pharmacodynamic relationship for CCR9 antagonists in the treatment of intestinal inflammation.

Topics: Administration, Oral; Animals; Calcium; Cell Line; Chemotaxis, Leukocyte; Crohn Disease; Gastrointestinal Agents; Humans; Ileitis; Inflammatory Bowel Diseases; Mice; Mice, Inbred C57BL; Radioligand Assay; Rats; Receptors, CCR; Sulfonamides; T-Lymphocytes; Tretinoin; Tumor Necrosis Factor-alpha