General anesthetics can exert significant adverse effects on the central nervous system. This study aimed to investigate whether repeated exposure to sevoflurane induces depression-like behaviors in postpartum rats. Pregnant rats were exposed to 3% sevoflurane for 2 h on gestational days 13-15. Emotional behaviors were assessed on postpartum days 1, 7, 14, and 21. Hippocampal protein levels associated with the AMPK/SIRT1/NLRP3 signaling pathway were analyzed by Western blotting. Microglial activation and inflammasome expression were analyzed by immunofluorescence, and cytokine levels (IL-1β, IL-18, TNF-α) by ELISA. To explore the role of the AMPK/SIRT1/NLRP3 pathway and neuroinflammation in postpartum maternal depression, rats were treated with AICAR (an AMPK agonist), MCC950 (an NLRP3 antagonist), and minocycline (a microglial activation inhibitor). Additionally, ketamine, with or without dorsomorphin (an AMPK antagonist), was administered to assess whether ketamine's antidepressant effects are mediated through this pathway. Sevoflurane-exposed rats exhibited behavioral impairments on postpartum day 1, including increased immobility in the forced swim test, prolonged feeding latency, reduced food consumption in the novelty-suppressed feeding test, and decreased movement in the open field test. These behaviors were accompanied by decreased AMPK/SIRT1 expression, NLRP3 inflammasome activation, and microglial activation in the hippocampus, resulting in significant inflammatory cytokine release. Treatment with AICAR, MCC950, minocycline, or ketamine alleviated these effects, while dorsomorphin reversed the antidepressant effects of ketamine. Our findings indicate that repeated sevoflurane exposure during mid-gestation induces depression-like behaviors in postpartum rats, and that ketamine alleviates these behaviors by reducing microglial neuroinflammation and NLRP3 inflammasome activation via the AMPK/SIRT1 signaling pathway.

2025-03-13·JOURNAL OF MEDICINAL CHEMISTRY

Discovery of DFV890, a Potent Sulfonimidamide-Containing NLRP3 Inflammasome Inhibitor

Article

作者: Byth, Kate F. ; Katz, Jason D. ; Braams, Simona ; Olhava, Edward J. ; Dean, Dennis ; Dekker, Carien ; Roush, William R. ; Opipari, Anthony W. ; Telling, Alissa ; Bradley, Sarah ; Lu, Xiaokang ; Stunden, James ; Shen, Dong-Ming ; Seidel, H. Martin ; Stutz, Andrea ; Venkatraman, Shankar ; Kitanovic, Ana ; Bertheloot, Damien ; Sanchez, Brian ; Franchi, Luigi ; Glick, Gary D. ; Hinniger, Alexandra ; El-Kattan, Ayman F. ; Ghosh, Shomir ; Winkler, David G.

The discovery of DFV890 ((R)-1), a potent and selective NLRP3 antagonist, is described. Replacement of the sulfonyl urea core from the first-generation NLRP3 antagonist CRID3 with a sulfonimidamide core afforded a novel and potent series of NLRP3 antagonists. The (R)-enantiomers of the sulfonimidamide series were found to be consistently more potent than structurally related sulfonyl ureas. Replacement of the furan unit of CRID3 with a 5-substituted thiazole unit led to DFV890 ((R)-1), which potently inhibited IL-1β production in THP-1 cells and in primary human cells, blocked multiple downstream effectors of NLRP3 activation, and substantially improved PK properties and significantly lowered the predicted human dose compared to that for CRID3. DFV890 ((R)-1) was also effective in an air pouch model of gout.

2023-03-01·The Journal of pathology

Cell death induced by NLRP3–palmitate axis impairs pulmonary damage tolerance and aggravates immunopathology during obesity‐tuberculosis comorbidity

Article

作者: Bonato, Vânia LD ; Corrêa, Giseli Furlan ; Fraga‐Silva, Thais FC ; de Oliveira, Rômulo Silva ; de Souza, Fernanda Mesquita ; Palma Albornoz, Sandra P ; Carlos, Daniela ; Gembre, Ana Flávia ; Ramalho, Leandra NZ ; Costa, Diego Luís ; de Almeida, Danilo C ; Takahashi, Viviani Nardini ; Rodrigues, Tamara S ; Câmara, Niels OS ; de Carvalho, Renan VH ; Medeiros, Alexandra I ; Sorgi, Carlos A ; Faccioli, Lucia H ; Zamboni, Dario S

Abstract:

A low‐grade and persistent inflammation, which is the hallmark of obesity, requires the participation of NLRP3 and cell death. During Mycobacterium tuberculosis infection, NLRP3 signaling is important for bacterial killing by macrophages in vitro but was shown to be dispensable for host protection in vivo. We hypothesized that during obesity‐tuberculosis (TB) comorbidity, NLRP3 signaling might play a detrimental role by inducing excessive inflammation. We employed a model of high‐fat‐diet‐induced obesity, followed by M. tuberculosis infection in C57BL/6 mice. Obese mice presented increased susceptibility to infection and pulmonary immunopathology compared to lean mice. Using treatment with NLRP3 antagonist and Nlrp3−/− mice, we showed that NLRP3 signaling promoted cell death, with no effect in bacterial loads. The levels of palmitate were higher in the lungs of obese infected mice compared to lean counterparts, and we observed that this lipid increased M. tuberculosis‐induced macrophage death in vitro, which was dependent on NLRP3 and caspase‐1. At the chronic phase, although lungs of obese Nlrp3−/− mice showed an indication of granuloma formation compared to obese wild‐type mice, there was no difference in the bacterial load. Our findings indicate that NLRP3 may be a potential target for host‐directed therapy to reduce initial and severe inflammation‐mediated disease and to treat comorbidity‐associated TB. © 2022 The Pathological Society of Great Britain and Ireland.

项与 NLRP3 antagonist(Cisen Pharmaceutical) 相关的新闻（医药）

2026-02-04

·EndPoints

Updated: Novartis expects generics to shave $4B from 2026 sales, as Entresto takes Q4 hit

Novartis said further generic erosion of three blockbuster medicines, including its top-selling heart failure drug Entresto, will leave a $4 billion hole in its sales this year. Generic competition started to make a mark in the fourth quarter, as Entresto sales plummeted 45% from the year-earlier period in constant currencies to $1.25 billion. Sales of thrombocytopenia treatment Promacta plunged 63% to $226 million, while blood cancer drug Tasigna declined 58% to $179 million. Even with the three generic rivals entering the market around mid-2025, Novartis was able to produce total fourth-quarter sales of $13.3 billion, relatively steady compared to the previous year. As for the coming full year, the company is predicting an increase in the low-single digits. “We expect to grow in 2026 through the largest patent expiries in Novartis history,” CEO Vas Narasimhan told the media. “This demonstrates the strength of our growth drivers and the strength of our pipeline.” Novartis’ revenue forecast suggests 2026 sales of $56.2 billion to $57.9 billion, Jefferies analysts wrote in a same-day note. At the same time, Novartis foresees core operating income declining by low-single digits, according to its latest earnings report . Full-year 2025 sales were up 8% from the year before, at $54.5 billion, supported by two products that passed the $1 billion mark for the first time. Blood cancer drug Scemblix pulled in $1.29 billion in 2025, up 85% from 2024. And sales of cholesterol medicine Leqvio grew 57% to hit $1.19 billion. Investors seemed to be reassured by these figures. The company’s share price remained flat on the Swiss exchange early Wednesday. On the pipeline side, Novartis discontinued several early- to mid-stage programs following a review. The majority of culled candidates were in Phase 1 development for cancer, namely: Novartis also dropped a candidate for tendinopathy called NGI226 that was in Phase 2 development. A company spokesperson wrote in an email that the cuts were “balanced by the addition of new projects entering our pipeline.” Novartis also slightly delayed some of its highly anticipated R&D milestones. It now expects to report Phase 3 data for pelacarsen in this year’s second half, as opposed to the first half, according to an earnings presentation . The drug is for certain patients who have elevated levels of lipoprotein(a). The company also said Phase 3 data for its rare kidney disease drug zigakibart would come in the first half of 2027, instead of this year. Novartis amended the protocol of a trial in IgA nephropathy so that kidney biomarker data would come at the same time as results on the primary endpoint of proteinuria, which is considered a more robust marker of kidney function. Elsewhere, Narasimhan said Novartis was still “very active” when it came to deals in China. Last month, it spent $50 million upfront to license a radiopharmaceutical candidate from Zonsen PepLib Biotech. Oncology will be a core focus for Novartis’ M&A deals going forward, Narasimhan told analysts on a separate earnings call. On the media call, the CEO described China’s biotech environment as “very important” and “exciting,” adding that US and European regulators could take lessons from some of the ways China has “streamlined regulatory oversight” and “modernized its clinical trial enrollment approach.” Novartis isn’t the first company to double down on its interest in China. Last month, AstraZeneca announced it would spend $15 billion on manufacturing and R&D projects in China through 2030. In December, Novartis said it had reached a deal with President Donald Trump’s administration to lower drug prices in the US. That deal included an agreement to launch future medicines with “comparable prices” across high-income countries. Narasimhan told analysts the company is “working through strategies” for anticipated launches, including its Sjögren’s disease candidate ianalumab, which is expected to launch in the G7 countries next year. Editor’s note: This article was updated to add comments from Novartis’ analyst call.

临床3期临床2期

2022-02-09

·BioSpace

Ventus will Aim $140 Million at Previously Undruggable Targets

Ventus Therapeutics has raised a significant war chest to fund its pipeline less than two years after launching to develop therapies aimed at diseases of the innate immune system. This morning, the company closed a $140 million Series C financing round, which will be used to drive its three lead programs into the clinic next year. This morning, Dr. Marcelo Bigal, president and chief executive officer of Waltham, Mass.-based Ventus, said the funds are expected to be sufficient to allow the company to accelerate the scaling of its ReSOLVE platform, which is being developed to address targets that were previously considered undruggable. According to Ventus, the ReSOLVE platform combines structural biology and protein science expertise with the company’s proprietary computational chemistry capabilities to address the current limitations of small molecule drug discovery. Ventus said the ReSOLVE platform can be leveraged to discover and characterize “previously unknown or poorly understood pockets on the surface of proteins” and small molecules that can bind to those pockets. The platform is designed to screen billions of compounds through computational programs that include structural information about a protein that enables the program to infer “multiple protein conformational states and the solvation structure of each conformation.” Additionally, the company aims to advance its lead drug candidates into the clinic. Versant Ventures-founded Ventus’ top candidates target critical modulators in the innate immune system, including NLRP3 (NLR pyrin domain-containing 3) and cGAS (cyclic GMP-AMP synthase). Both of these targets have been extensively implicated in human disease. NLRP3 is a key mediator of pro-inflammatory cytokines IL-1b and IL-18 and is targeted in conditions where inflammation is the key driver of pathology. Lead asset VENT-01 is a peripherally restricted small molecule inhibitor compound that targets NLRP3. The second Ventus asset is a brain-penetrant NLRP3 inhibitor, while the company’s third candidate targets cGAS, a key regulator of the cGAS/stimulator of interferon genes (STING) pathway. In addition to advancing its lead candidates, Ventus intends to use a portion of the Series C proceeds to expand its research and development staff to support additional pipeline programs, providing potential opportunities for both partnerships and internal growth. The Series C was co-led by SoftBank Vision Fund 2 and RA Capital Management. Other participants include Qatar Investment Authority, Andreessen Horowitz, BVF Partners L.P., Casdin Capital, Cormorant Asset Management, Fonds de solidarité FTQ, Alexandria Venture Investments, GV (formerly Google Ventures), and founding investor Versant Ventures. John Cassidy, investor for SoftBank Investment Advisers and a new member of the Ventus Therapeutics board of directors, said the ReSOLVE platform makes it “quicker and more cost-effective to identify molecular targets from an almost infinite library of compounds.” He expressed excitement about the partnership with Ventus as the company moves toward the clinic with its assets. The $140 million Series C comes less than a year after the company raised $100 million in a Series B financing round.

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