Discovery of pyrimidine-5-carboxamide derivatives as novel salt-inducible kinases (SIKs) inhibitors for inflammatory bowel disease (IBD) treatment.

Abstract

Salt-inducible kinases (SIKs) play a crucial role in inflammation process, acting as molecular switches that regulate the transformation of M1/M2 macrophages. HG-9-91-01 is a SIKs inhibitor with potent inhibitory activity against SIKs in the nanomolar range. However, its poor drug-like properties, including a rapid elimination rate, low in vivo exposure and high plasma protein binding rate, have hindered further research and clinical application. To improve the drug-like properties of HG-9-91-01, a series of pyrimidine-5-carboxamide derivatives were designed and synthesized through a molecular hybridization strategy. The most promising compound 8h was obtained with favorable activity and selectivity on SIK1/2, excellent metabolic stability in human liver microsome, enhanced in vivo exposure and suitable plasma protein binding rate. Mechanism research showed that compound 8h significantly up-regulated the expression of anti-inflammatory cytokine IL-10 and reduced the expression of pro-inflammatory cytokine IL-12 in bone marrow-derived macrophages. Furthermore, it significantly elevated expression of cAMP response element-binding protein (CREB) target genes IL-10, c-FOS and Nurr77. Compound 8h also induced the translocation of CREB-regulated transcriptional coactivator 3 (CRTC3) and elevated the expression of LIGHT, SPHK1 and Arginase 1. Additionally, compound 8h demonstrated excellent anti-inflammatory effects in a DSS-induced colitis model. Generally, this research indicated that compound 8h has the potential to be developed as an anti-inflammatory drug candidate.

• Authors: Xiaoying Cai, Lun Wang, Yuyao Yi, Dexin Deng, Mingsong Shi, Minghai Tang, Na Li, Haoche Wei, Ruijia Zhang, Kaiyue Su, Haoyu Ye, Lijuan Chen
• Journal: European journal of medicinal chemistry (Eur J Med Chem) Vol. 256 Pg. 115469 (Aug 05 2023) ISSN: 1768-3254 [Electronic] France
• PMID: 37178481 (Publication Type: Journal Article)
• Copyright: Copyright © 2023. Published by Elsevier Masson SAS.

Chemical References

• Interleukin-10
• HG-9-91-01
• Protein Serine-Threonine Kinases
• Pyrimidines
• Cytokines

Topics

• Humans
• Interleukin-10
• Protein Serine-Threonine Kinases
• Pyrimidines (chemistry)
• Inflammatory Bowel Diseases (drug therapy)
• Cytokines (metabolism)