An SAR study that identified a series of thienopyridine-based potent IkappaB Kinase beta (IKKbeta) inhibitors is described. With focuses on the structural optimization at C4 and C6 of structure 1 (Fig. 1), the study reveals that small alkyl and certain aromatic groups are preferred at C4, whereas polar groups with proper orientation at C6 efficiently enhance compound potency. The most potent analogues inhibit IKKbeta with IC50s as low as 40 nM, suppress LPS-induced TNF-alpha production in vitro and in vivo, display good kinase selectivity profiles, and are active in a HeLa cell NF-kappaB reporter gene assay, demonstrating that they directly interfere with the NF-kappaB signaling pathway.

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bmcl.2009.08.054DOI Listing

Publication Analysis

Top Keywords

potent ikappab
8
ikappab kinase
8
kinase beta
8
discovery thienopyridine
4
thienopyridine analogues
4
analogues potent
4
beta inhibitors
4
inhibitors sar
4
sar study
4
study identified
4

Similar Publications

The combination of RL-QN15 and OH-CATH30 promotes the repair of acne via the TLR2/NF-κB pathway.

Eur J Pharmacol

December 2024

Department of Anatomy and Histology & Embryology, Faculty of Basic Medical Science, Kunming Medical University, Kunming, Yunnan, 650500, China. Electronic address:

Acne is a prevalent and chronic inflammatory skin disease, and its treatment remains a huge clinical challenge. In the present study, we evaluated the therapeutic potential of combining the peptides RL-QN15 and OH-CATH30 for the treatment of acne in mice. Results indicated that the topical application of RL-QN15 and OH-CATH30 significantly inhibited the proliferation of Propionibacterium acnes (P.

View Article and Find Full Text PDF

Non-septic shock is a serious condition leading to multiple organ dysfunction. Although targeting the mammalian target of the rapamycin complex 1 (mTORC1) signaling pathway exerts potent anti-inflammatory activity, little is known about mTORC2's contribution to non-septic shock. Thus, our research aims to investigate mTORC2's contribution and associated changes of IκB kinase (IKKα)/inhibitor κB (IκB-α)/nuclear factor-ĸB (NF-κB) pathway on Zymosan (ZYM)-induced non-septic rat model using the novel mTORC2 selective inhibitor JR-AB2-011.

View Article and Find Full Text PDF

3-(2-Trifluoromethyl-3-aryl-4H-chromen-4-yl)-1H-indoles: Mastering anti-inflammation and analgesia while mitigating gastrointestinal side effects.

Bioorg Chem

December 2024

State Key Laboratory of Fine Chemicals, Department of Pharmaceutical Engineering, School of Chemical Engineering, Dalian University of Technology, 2 Linggong Road, Dalian 116024, PR China. Electronic address:

A series of 3-(2-trifluoromethyl-3-aryl-4H-chromen-4-yl)-1H-indoles (5-1 to 5-29) were developed and characterized. Most of compounds were found to be potent for inhibiting the production of NO in LPS-induced RAW264.7 cells, of which 3-(3-(4-chlorophenyl)-6-methoxy-2-(trifluoromethyl)-4H-chromen-4-yl)-1H-indole (5-25) was the most optimal (IC = 4.

View Article and Find Full Text PDF

One of the main causes of death worldwide is lung cancer, which is largely caused by cigarette smoking. The crucial transcription factor NF-κB, which controls inflammatory responses and various cellular processes, is a constitutively present cytoplasmic protein strictly regulated by inhibitors like IκB proteins. Upon activation by external stimuli, it undergoes phosphorylation, translocates into the nucleus, and modulates the expression of specific genes.

View Article and Find Full Text PDF

Phosphatidylserine-functional polydimethylsiloxane substrates regulate macrophage M2 polarization via modulus-dependent NF-κB/PPARγ pathway.

Biomater Adv

December 2024

Department of Materials Science and Engineering, College of Chemistry and Materials, Jinan University, Guangzhou 510632, PR China. Electronic address:

Macrophages, highly plastic innate immune cells, critically influence the success of implantable devices by responding to biochemical and physical cues. However, the mechanisms underlying their synergistic regulation of macrophage polarization on implant surfaces remain poorly understood. Therefore, we constructed anti-inflammatory phosphatidylserine (PS) modified polydimethylsiloxane (PDMS) substrates with low, medium, and high modulus (1-100 kPa) to investigate the combined effects and underlying mechanisms of substrate modulus and biochemical signal on macrophage polarization.

View Article and Find Full Text PDF

Want AI Summaries of new PubMed Abstracts delivered to your In-box?

Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!