Inflammatory bowel disease (IBD) is a chronic relapsing inflammatory disease. It has a high incidence in western developed countries. The incidence of IBD in China has been increasing year by year, and it has become a common disease in the digestive system. IBD mainly includes Ulcerative colitis (UC) and Crohn's disease (CD), and its pathogenesis is still unclear. Current research is generally considered to be related to genetic, environmental and immune abnormalities: Genetic and environmental factors induce activation of the intestinal immune system, triggering an excessive inflammatory response and continuing to progress, thereby destroying the intestinal wall and producing clinical signs of IBD. So far, there is no drug to completely cure IBD. Monoclonal antibody is currently the most effective drug for relieving IBD symptoms. However, all drugs need to be administered by injection. Patients have poor compliance, high cost of treatment, and long-term use is prone to drug resistance. Adverse reactions, therefore, small molecule drugs for IBD have become a research hotspot in this field in recent years. The IBD drugs in clinical research are reviewed.
1.S1P receptor modulator
Phosphorylation of intracellular sphingosine forms sphingosine-1-phosphate (S1P), which is controlled by two sphingosine kinases, SK1 and SK2, which produce S1P that binds to the S1P receptor subtype (S1PR1 to S1PR5) Prevent lymphocytes from entering the bloodstream, thereby reducing the inflammatory response. Fingolimod is a sphingosine analogue that is activated by SK2 phosphorylation to form activated phosphorylated fingolimod, an agonist of S1PRs (except S1PR2), capable of inducing immunosuppression, and has been approved for multiple A drug for sclerosis (MS), but it is found to have a risk of heart rate mitigation in clinical use, possibly related to activation of S1PR1 and activation of other S1P receptors (especially S1PR3). Fingolimod has a unique pharmacokinetic property, its absorption is slow, peak plasma concentration is reached 8-36 h after oral administration, and it has a high volume of distribution and half-life in vivo (about 108 h). Fingolimod's dosing regimen is once a day, and it takes about 4 weeks to reach a steady-state plasma concentration, which increases the concentration of the drug in the tissue by 11-19 times compared to the first dose. In terms of IBD drug development, fingolimod showed good efficacy in a variety of mouse models of IBD. Structural modification of the fatty chain of fingolimod, replacing the fatty chain fragment with an aromatic ring to obtain KRP203 (Kyorin Pharmaceutical), which acts in a similar manner to fingolimod, in the case of sodium dextran sulfate (DSS) and IL-10 The gene knockout IBD mouse model showed better efficacy. At present, KRP203 has entered the phase II clinical trial, but the clinical development of the drug in Europe and Japan has been discontinued. The reason has not been reported. Fingolimod's structural analog, Amiselimod (MT-1303), is also in Phase II clinical research, but Biogen has suspended its clinical studies for CD based on the company's product line layout optimization. Ozanimod, a selective S1PR1 and S1PR5 agonist, was discovered by Receptos and is currently being advanced by Celgene for Phase II clinical trials for the treatment of UC and CD. In addition, Etrasimod (APD334, Arena Pharmaceuticals) is a selective agonist of S1PR1, S1PR4 and S1PR5 and is currently undergoing phase II clinical studies by Arena Pharmaceuticals for the treatment of UC.
2.JAK inhibitor
In November 2012, the FDA approved the JAK inhibitor Tofacitinib (Xeljanz, Pfizer) for the treatment of active rheumatoid arthritis (RA) and adult patients who are ineffective or intolerant to methotrexate and other antirheumatic drugs. Tofacitinib, a potent inhibitor of JAK1 and JAK3, has a slightly weaker inhibitory effect on JAK2 and therefore blocks the production of various key cytokines (IL-2, IL-6, IFN-g and IL-17) that cause the onset of IBD. Tofacitinib was used in phase II clinical trials for patients with moderate to severe UC (OCTAVE trial). From 2012 to 2016, Pfizer also conducted a number of Phase III clinical trials for moderate to severe UC, and Tofacitinib showed significant efficacy relative to the placebo group. In contrast, the results of phase II clinical trials of Tofacitinib in patients with CD were not satisfactory, although some biochemical indicators improved in the high-dose group, but the overall treatment effect was not significantly different from the placebo group. Pfizer has discontinued Phase III clinical trials of Tofacitinib for CD therapy. In addition, Tofacitinib showed higher side effects than the placebo group in clinical trials, such as severe infections, which may be related to its low selectivity. For example, inhibition of JAK2 is thought to cause adverse reactions such as anemia, thrombocytopenia, and neutropenia. Therefore, the development of highly selective JAK inhibitors for the treatment of IBD will improve the safety of clinical use to some extent. Upadacitinib is a selective JAK1 inhibitor, which has a significant efficacy compared to placebo in a phase II clinical study of moderate to severe CD, and is safe in clinical safety associated with the drug's treatment of rheumatoid arthritis. similar.
Peficitinib is a selective JAK3 inhibitor and has completed a Phase II clinical trial of UC. However, Phase III clinical trials for UC have been discontinued. Interestingly, unlike other JAK inhibitors, clinical trials of Peficitinib have focused on patients with UC (rather than CD). Astellas is conducting a phase III clinical study of rheumatoid arthritis after discontinuing Phase III clinical trials of UC.
3.CCR9 antagonist
CCR9 is a chemokine receptor expressed on memory/effector CD4+ T cells and selectively binds to the chemokine CCL25. CCL25 is a cytokine mainly expressed in thymocytes and intestinal epithelial cells. When inflammation occurs in the intestine, its expression is significantly increased, and the interaction of lymphocytes into intestinal tissues is driven by interaction with its receptor CCR9. By inhibiting the interaction of CCR9 and CCL25, preventing the movement of lymphocytes into the intestinal tissue, thereby alleviating intestinal inflammation, can be used as a treatment for CD.
Vercirnon is an oral small molecule CCR9 selective antagonist developed by Glaxo Smith Kline for potential treatment of intestinal inflammatory diseases including CD and celiac disease. Vercirnon may accelerate the elimination of intestinal inflammatory T cells, so it is possible to promote clinical improvement by reducing the duration of IBD-related emergencies. Although Vercirnon showed good efficacy in the phase II clinical trial of moderate to severe CD, it did not have a significant effect in the phase III clinical trial compared to the placebo group, causing its subsequent development (including its clinical trial of UC) to be discontinued. . The reason for its failure is considered to be the problem of oral and subcutaneous injection pharmacokinetics caused by its poor physical and chemical properties, so that CCR9 cannot be continuously inhibited. Therefore, it is necessary to carry out rational drug design for its physical and chemical properties. And the prospects.
4. -4-4 integrin inhibitor
Integrin on the surface of immune cells mediates its close adhesion to endothelial cells and mucosal epithelial cells. By inhibiting the activity of integrin, it is possible to inhibit the process of migration and accumulation of immune cells to the vicinity of the pathogen tissue, thereby improving inflammation. AJM300 is an orally active small molecule inhibitor of alpha-4 integrin, similar to the commercially available α4β7 integrin inhibitor Vedolizumab, which blocks lymphocytes (via adhesion molecules) from entering the inflammatory bowel. AJM300 is effective against colitis in IL-10 deficient T cell metastasis model mice. In phase II clinical trials, AJM300 has significant efficacy in the induction therapy of active UC patients. At present, AJM300 has completed Phase II clinical trials in active moderate UC adult patients who are not sensitive or intolerant to mesalazine or glucocorticoid in Japan. However, safety problems (ie progressive multifocal leukoencephalopathy) (PML)) may be a potential challenge.
5. Immunomodulator
Linomide (Roquinimex) is a quinoline derivative immunopotentiator that increases NK cell activity and cytotoxicity of macrophages. It also inhibits angiogenesis and reduces the production of TNF-[alpha]. Linomide has been used to treat certain cancers (including adjuvant treatment after bone marrow transplantation in acute leukemia) and autoimmune diseases such as multiple sclerosis and newly developed type 1 diabetes. However, due to its severe cardiovascular toxicity, many trials of the drug have been terminated. Laquinimod is a structural analog of Linomide and a potential orally available small molecule immunomodulator developed by Teva Pharmaceuticals for the treatment of various autoimmune diseases. The researchers found that laquinimod significantly improved colitis in IL-10-deficient mice, and that the reduction in inflammation was associated with the restoration of colon barrier function and the reduction of NF-kB signaling. A recent Phase II study demonstrated that laquinimod is effective and safe in patients with CD, and that it has also entered Phase III clinical trials for the treatment of moderate to severe CD.
Vidofludimus (a novel immunomodulator from 4SCAG) has a dual mechanism of action. On the one hand, Vidofludimus can reduce IL-17 production in the colon by inhibiting STAT3 and NF-kB activation; on the other hand, Vidofludimus can also act as DHODH (dihydrogen emulsion). An acid dehydrogenase inhibitor that inhibits the increase of T cells in the colon. Vidofludimus has significant efficacy in the DSS and TNBS mouse models as well as in the TNBS-induced rat enteritis model. Vidofludimus has shown good efficacy and safety in the IIa clinical trial of IBD, including CD and UC patients, with a response rate of 88.5% in patients with IBD.
6. Mucosal barrier enhancer
Developed by Lipid Therapeutics, LT-102 is a phospholipid agent that releases phosphatidylcholine. The mucous layer of the gastrointestinal tract is mainly composed of water, glycoproteins, lipids, other proteins and nucleic acids. Although phospholipids are a minor component of GI mucus, their hydrophobic surfaces established by virtue of amphiphilicity are indispensable for maintaining a complete barrier function. Surface phosphatidylcholine (PC) is the main mucin phospholipid. Compared with healthy people, UC patients have found that phosphatidylcholine (PC) in mucus of UC patients is significantly reduced and independent of inflammatory status. The lack of PC can lead to a decrease in surface hydrophobicity, leading to the intrusion of harmful substances in the lumen. However, PC is also involved in a variety of potential pro-inflammatory pathways, including tumor necrosis factor-alpha (TNF-alpha) signaling, activation of NF-kB cytokine expression, and mitogen-activated protein kinase. According to its inherent structure in the colonic mucosa, if PC reconstruction in colonic mucus of UC patients (via LT-102) can help restore mucus structure and density in UC patients, it can improve mucosal barrier function and prevent inflammation in UC patients. LT-102 is mainly used to improve the mucosal barrier function of patients with mild to moderate UC. It is currently in phase III clinical study.
As a chronic recurrent digestive system, IBD is not well defined and has no cure. Although the rise of antibody drugs has been very successful in the treatment of IBD, the development of small molecule IBD drugs has become a problem because of its poor patient compliance, high cost of treatment, and long-term use of drug resistance and adverse reactions. Problems that patients, doctors, pharmaceutical companies, and researchers pay close attention to can be expected to be developed in the near future for small molecule IBD drugs, and benefit IBD patients, in addition to the IBD candidate compounds in clinical studies described in this article. The follow-up will continue to summarize the potential compounds for small molecule treatment of IBD in preclinical studies.
