Discovery of 3-(4-(2-((1<i>H</i>-Indol-5-yl)amino)-5-fluoropyrimidin-4-yl)-1<i>H</i>-pyrazol-1-yl)propanenitrile Derivatives as Selective TYK2 Inhibitors for the Treatment of Inflammatory Bowel Disease

Self Cite

In this study, we described a series of 2,8-diazaspiro[4.5]decan-1-one derivatives as selective TYK2/JAK1 inhibitors. Systematic exploration of the structure–activity relationship through the introduction of spirocyclic scaffolds based on the reported selective TYK2 inhibitor 14l led to the discovery of the superior derivative compound 48. Compound 48 showed excellent potency on TYK2/JAK1 kinases with IC50 values of 6 and 37 nM, respectively, and exhibited more than 23-fold selectivity for JAK2. Compound 48 also demonstrated excellent metabolic stability and more potent anti-inflammatory efficacy than tofacitinib in acute ulcerative colitis models. Moreover, the excellent anti-inflammatory effect of compound 48 was mediated by regulating the expression of related TYK2/JAK1-regulated genes, as well as the formation of Th1, Th2, and Th17 cells. Taken together, these findings suggest that compound 48 is a selective dual TYK2/JAK inhibitor, deserving to be developed as a clinical candidate.

Section: ■ Introductionmentioning

confidence: 94%

Section: Introductionmentioning

confidence: 99%

Identification of a Novel 2,8-Diazaspiro[4.5]decan-1-one Derivative as a Potent and Selective Dual TYK2/JAK1 Inhibitor for the Treatment of Inflammatory Bowel Disease

Cui

Tang

et al. 2022

Self Cite

“…More importantly, anti-TNF-α biologics may exhibit serious side effects, including infection, cancer, and death. Therefore, identifying effective and safe inflammatory targets and developing corresponding drugs is an urgent task for treatment of IBD. − …”

Section: Introductionmentioning

confidence: 99%

Discovery and Anti-Inflammatory Activity Evaluation of a Novel CDK8 Inhibitor through Upregulation of IL-10 for the Treatment of Inflammatory Bowel Disease In Vivo

Liu

2022

Increasing the anti-inflammatory cytokine interleukin-10 (IL-10) level is a promising strategy to suppress the progression of pathogenic inflammation including inflammatory bowel disease (IBD). Since cyclin-dependent kinase 8 (CDK8) inhibition can upregulate IL-10 abundance in activated myeloid-derived dendritic cells, it is considered to be an effective target for IBD treatment. Here, the complete discovery process of a novel CDK8 inhibitor as an anti-inflammatory agent was described. Starting with wogonin, structure-based optimization and structure−activity relationship (SAR) study were comprehensively carried out, and then lead compound 85 (N-(2-ethylphenyl)-5-(4-(piperazine-1carbonyl)phenyl)nicotinamide) was developed as a potent druglike CDK8 inhibitor upregulating IL-10 both in vivo and in vitro. Also, compound 85 (with CDK8 IC 50 = 56 nM, IL-10 enhancement rate 88%) exhibited effective anti-inflammatory activity in an animal model of IBD. These results confirmed that certain CDK8 inhibitor could be used as an effective anti-IBD drug.

“…Ulcerative colitis (UC), emerging as a public health challenge worldwide, is an idiopathic chronic inflammatory bowel disease (IBD) causing bloody diarrhea and inflammatory alterations . The incidence and prevalence of ulcerative colitis have been increasing over time worldwide. , Recently, clinical statistics showed that some UC patients could progress toward major dysplasia of the intestinal glands, and ultimately toward malignant states such as carcinogenesis and cancer. , Various types of drugs have been used for the treatment of UC depending on the severity and the extent of the disease, such as 5-aminosalicylic acid (ASA), corticosteroids, immunomodulators, calcineurin agents, and biologics. , Among the biologics, anti-TNF-α agents are well studied and extensively used in moderate-to-severe UC patients. − Unfortunately, the disadvantages coming from these antibodies are also obvious. In addition to the high cost and requirement of intravenous injection, such treatment could elicit an autoimmune response, potentially weakening patients’ immune defense. , Therefore, small-molecule drugs may serve as better alternatives in this case to modulate tumor necrosis factor α (TNF-α) production .…”

Section: Introductionmentioning

confidence: 99%

“…4,5 Various types of drugs have been used for the treatment of UC depending on the severity and the extent of the disease, such as 5-aminosalicylic acid (ASA), corticosteroids, immunomodulators, calcineurin agents, and biologics. 6,7 Among the biologics, anti-TNF-α agents are well studied and extensively used in moderate-to-severe UC patients. 8−10 Unfortunately, the disadvantages coming from these antibodies are also obvious.…”

Section: Introductionmentioning

confidence: 99%

Discovery of First-in-Class TAK1–MKK3 Protein–Protein Interaction (PPI) Inhibitor (R)-STU104 for the Treatment of Ulcerative Colitis through Modulating TNF-α Production

Tang

Ning

et al. 2022

Tumor necrosis factor α (TNF-α) has been demonstrated to be a therapeutic target for autoimmune diseases. However, this biological therapy exhibits some inevitable disadvantages, such as risk of infection. Thus, small-molecule alternatives by targeting TNF-α production signaling pathway are still in demand. Herein, we describe the design, synthesis, and structure–activity relationships of 3-aryindanone compounds regarding their modulation of TNF-α production. Among them, ( R )-STU104 exhibited the most potent inhibitory activity on TNF-α production, which suppressed the TAK1/MKK3/p38/MnK1/MK2/elF4E signal pathways through binding with MKK3 and disrupting the TAK1 phosphorylating MKK3. As a result, ( R )-STU104 demonstrated remarkable dose–effect relationships on both acute and chronic mouse UC models. In addition to its good pharmacokinetic (PK) and safety profile, ( R )-STU104 showed better anti-UC efficacy in vivo at 10 mg/kg/d than mesalazine at the dose of 50 mg/kg/d. These results suggested that TAK1–MKK3 interaction inhibitors could be potentially utilized for the treatment of UC.