Discovery of novel small molecule TLR4 inhibitors as potent anti-inflammatory agents. 2018

Yao Xu, and Shujun Chen, and Ying Cao, and Pingzheng Zhou, and Zhipeng Chen, and Kui Cheng
Guangdong Provincial Key Laboratory of New Drug Screening and Guangzhou Key Laboratory of Drug Research for Emerging Virus Prevention and Treatment, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, China.

Toll-like receptor 4 (TLR4) initiates innate immune response to release inflammatory cytokines and has been pathologically linked to variety of inflammatory diseases. Recently, we found that Carvedilol, as the classic anti-heart failure and anti-inflammatory clinic drug, could inhibit the TLR4 signaling in the TLR4 overexpressed cells. Herein, we have designed and synthesized a small library of novel Carvedilol derivatives and investigated their potential inhibitory activity. The results indicate that the most potent compound 8a (SMU-XY3) could effectively inhibited TLR4 protein and the LPS triggered alkaline phosphatase signaling in HEK-Blue hTLR4 cells. It down regulated the nitric oxide (NO) in both RAW264.7 cells and BV-2 microglial cells, in addition to blocking the TNF-α signaling in ex-vivo human peripheral blood mononuclear cells (PBMC). More interestingly, 8a shows higher affinity to hyperpolarization-activated cyclic nucleotide-gated 4 (HCN4) over HCN2, which probably indicates the new application of TLR4 inhibitor 8a in heart failure, coronary heart disease, and other inflammatory diseases.

UI MeSH Term Description Entries
D007963 Leukocytes, Mononuclear Mature LYMPHOCYTES and MONOCYTES transported by the blood to the body's extravascular space. They are morphologically distinguishable from mature granulocytic leukocytes by their large, non-lobed nuclei and lack of coarse, heavily stained cytoplasmic granules. Mononuclear Leukocyte,Mononuclear Leukocytes,PBMC Peripheral Blood Mononuclear Cells,Peripheral Blood Human Mononuclear Cells,Peripheral Blood Mononuclear Cell,Peripheral Blood Mononuclear Cells,Leukocyte, Mononuclear
D009569 Nitric Oxide A free radical gas produced endogenously by a variety of mammalian cells, synthesized from ARGININE by NITRIC OXIDE SYNTHASE. Nitric oxide is one of the ENDOTHELIUM-DEPENDENT RELAXING FACTORS released by the vascular endothelium and mediates VASODILATION. It also inhibits platelet aggregation, induces disaggregation of aggregated platelets, and inhibits platelet adhesion to the vascular endothelium. Nitric oxide activates cytosolic GUANYLATE CYCLASE and thus elevates intracellular levels of CYCLIC GMP. Endogenous Nitrate Vasodilator,Mononitrogen Monoxide,Nitric Oxide, Endothelium-Derived,Nitrogen Monoxide,Endothelium-Derived Nitric Oxide,Monoxide, Mononitrogen,Monoxide, Nitrogen,Nitrate Vasodilator, Endogenous,Nitric Oxide, Endothelium Derived,Oxide, Nitric,Vasodilator, Endogenous Nitrate
D011412 Propanolamines AMINO ALCOHOLS containing the propanolamine (NH2CH2CHOHCH2) group and its derivatives. Aminopropanols
D002227 Carbazoles Benzo-indoles similar to CARBOLINES which are pyrido-indoles. In plants, carbazoles are derived from indole and form some of the INDOLE ALKALOIDS.
D002460 Cell Line Established cell cultures that have the potential to propagate indefinitely. Cell Lines,Line, Cell,Lines, Cell
D004305 Dose-Response Relationship, Drug The relationship between the dose of an administered drug and the response of the organism to the drug. Dose Response Relationship, Drug,Dose-Response Relationships, Drug,Drug Dose-Response Relationship,Drug Dose-Response Relationships,Relationship, Drug Dose-Response,Relationships, Drug Dose-Response
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000067996 RAW 264.7 Cells A transformed macrophage cell line isolated from ASCITES of mice infected with ABELSON MURINE LEUKEMIA VIRUS. RAW 264.7 Cell Line,264.7 Cell, RAW,264.7 Cells, RAW,Cell, RAW 264.7,Cells, RAW 264.7,RAW 264.7 Cell
D000077261 Carvedilol A carbazole and propanol derivative that acts as a non-cardioselective beta blocker and vasodilator. It has blocking activity for ALPHA 1 ADRENERGIC RECEPTORS and, at higher doses, may function as a blocker of CALCIUM CHANNELS; it also has antioxidant properties. Carvedilol is used in the treatment of HYPERTENSION; ANGINA PECTORIS; and HEART FAILURE. It can also reduce the risk of death following MYOCARDIAL INFARCTION. BM 14190,BM-14190,Carvedilol Hydrochloride,Carvedilol, (+),Carvedilol, (+)-isomer,Carvedilol, (+-)-isomer,Carvedilol, (-),Carvedilol, (-)-isomer,Carvedilol, (R)-isomer,Carvedilol, (S)-isomer,Carvedilol, 14C-labeled,Coreg,Coropres,Dilatrend,Eucardic,Kredex,Querto,14C-labeled Carvedilol,BM14190,Carvedilol, 14C labeled
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia

Related Publications

Yao Xu, and Shujun Chen, and Ying Cao, and Pingzheng Zhou, and Zhipeng Chen, and Kui Cheng
January 2021, Journal of medicinal chemistry,
Yao Xu, and Shujun Chen, and Ying Cao, and Pingzheng Zhou, and Zhipeng Chen, and Kui Cheng
May 2016, European journal of medicinal chemistry,
Yao Xu, and Shujun Chen, and Ying Cao, and Pingzheng Zhou, and Zhipeng Chen, and Kui Cheng
March 2008, Bioorganic & medicinal chemistry letters,
Yao Xu, and Shujun Chen, and Ying Cao, and Pingzheng Zhou, and Zhipeng Chen, and Kui Cheng
January 2023, International journal of molecular sciences,
Yao Xu, and Shujun Chen, and Ying Cao, and Pingzheng Zhou, and Zhipeng Chen, and Kui Cheng
August 2023, Journal of natural products,
Yao Xu, and Shujun Chen, and Ying Cao, and Pingzheng Zhou, and Zhipeng Chen, and Kui Cheng
December 2022, European journal of medicinal chemistry,
Yao Xu, and Shujun Chen, and Ying Cao, and Pingzheng Zhou, and Zhipeng Chen, and Kui Cheng
December 2018, Journal of enzyme inhibition and medicinal chemistry,
Yao Xu, and Shujun Chen, and Ying Cao, and Pingzheng Zhou, and Zhipeng Chen, and Kui Cheng
January 2023, International journal of molecular sciences,
Yao Xu, and Shujun Chen, and Ying Cao, and Pingzheng Zhou, and Zhipeng Chen, and Kui Cheng
November 2006, Medicinal chemistry (Shariqah (United Arab Emirates)),
Yao Xu, and Shujun Chen, and Ying Cao, and Pingzheng Zhou, and Zhipeng Chen, and Kui Cheng
May 2022, Journal of medicinal chemistry,
Copied contents to your clipboard!