Women who develop preeclampsia during pregnancy are more likely to develop and die of cardiovascular disease later in life, even if they are otherwise healthy. The reason why this occurs is unclear but may be related to impaired endothelial function and dysregulation of the angiotensin system that occurs during the preeclamptic pregnancy and persists postpartum, despite the remission of clinical symptoms. The purpose of this investigation is to determine the mechanisms contributing to this lasting blood vessel damage caused by reduced endothelial function in women who have had preeclampsia compared to women who had a healthy pregnancy. Identification of these mechanisms and treatment strategies may lead to better clinical management of cardiovascular disease risk in these women.
The purpose of this study is to examine the microvascular differences in women who have had preeclampsia following activation of protective angiotensin receptors in the skin. This will help increase understanding of the mechanisms of angiotensin II receptors in these women, and how activation of these receptors may restore microvascular function.
In this study, the investigators use the blood vessels in the skin as a representative vascular bed for examining mechanisms of microvascular dysfunction in humans. Using a minimally invasive technique (intradermal microdialysis for the local delivery of pharmaceutical agents) the investigators examine the blood vessels in a dime-sized area of the skin.

开始日期2023-06-28

申办/合作机构

University of Iowa

100 项与 Compound 21(UIOWA) 相关的临床结果

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100 项与 Compound 21(UIOWA) 相关的转化医学

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100 项与 Compound 21(UIOWA) 相关的专利（医药）

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项与 Compound 21(UIOWA) 相关的文献（医药）

2025-06-01·BIOORGANIC CHEMISTRY

Discovery of a novel Thiazole amide inhibitor of Inflammasome and Pyroptosis pathways

Article

作者: Wang, Ke ; Yu, Quanwei ; Chen, Zhiping ; Wang, Yuxi ; Bai, Chenli ; Dai, Zhen ; Li, Yong ; Ding, Jianjun ; Liao, Jihong

Upon the activation of inflammasomes, inflammatory caspases cleave and activate gasdermin D (GSDMD), leading to pore formation that causes cell membrane rupture and amplifies downstream inflammatory responses. Dysregulated inflammasome activation and pyroptosis signaling pathways are implicated in numerous inflammatory diseases. In our work, a set of novel thiazole amide compounds with inhibitory activity against NLRP3 inflammasome-induced pyroptosis was identified. Of all the compounds tested, compound 21 demonstrated the most potent anti-pyroptotic effects. It suppressed GSDMD cleavage and decreased IL-1β and lactate dehydrogenase (LDH) release in a concentration-dependent manner. Compound 21 bound to NLRP3 protein and increased the thermal stability of NLRP3 concentration-dependently. The molecular docking and dynamics simulations revealed that compound 21 binds to the NLRP3 protein's active site, suppressing inflammasome activation. Further investigations showed that compound 21 also partially blocked upstream NF-κB signaling and downstream GSDMD N-terminal domain (GSDMD-NT) oligomerization, which explains its broad inhibitory effects on pyroptosis driven by multiple inflammasomes. Overall, this study presents a promising thiazole amide compound with inhibitory activity against inflammasome activation and subsequent pyroptosis, warranting further exploration.

2025-05-01·HYPERTENSION

Reduced AT ₂ R Signaling Contributes to Endothelial Dysfunction After Preeclampsia

Article

作者: Santillan, Mark K. ; Schwartz, Kelsey S. ; Stanhewicz, Anna E. ; Jalal, Diana I. ; Sun, Mingyao

BACKGROUND::

Women who had preeclampsia (a history of preeclampsia) have a >4-fold risk of developing cardiovascular disease compared with women who had an uncomplicated pregnancy (history of healthy pregnancy). Despite the remission of clinical symptoms after pregnancy, vascular endothelial dysfunction persists postpartum, mediated in part by exaggerated Ang II (angiotensin II)–mediated constriction. However, the role of vasodilatory AT 2 Rs (Ang II type 2 receptors) in this dysfunction is unknown. We examined the functional role of AT 2 R in the microvasculature postpartum and whether acute activation of AT 2 R improves microvascular endothelial function after preeclampsia.

METHODS::

Overall, 24 women (n=12/group) participated. We measured cutaneous vascular conductance responses to (1) graded infusion of compound 21 (AT 2 R agonist; 10 −14 –10 −8 M) alone or with NG-nitro-l-arginine methyl ester (NO synthase inhibitor; 15 mM) and (2) a standardized local heating protocol in control and 10 −11 M compound 21–treated sites. Expression of Ang II receptor subtypes I and II in biopsied venous endothelial cells was quantified using immunofluorescence.

RESULTS::

AT 2 R-mediated dilation ( P <0.01) and the NO-dependent contribution ( P =0.003) of this response were reduced in women with a history of preeclampsia. Endothelial AT 2 R expression was lower in women with a history of preeclampsia ( P <0.01), but there were no differences in endothelial AT 1 R (Ang II type 1 receptor) expression ( P >0.05). Acute activation of AT 2 R during local heating improved endothelium ( P <0.01) and NO-dependent ( P <0.01) dilation in women with a history of preeclampsia but had no effect in women with a history of healthy pregnancy (both P >0.05).

CONCLUSIONS::

Reductions in AT 2 R-mediated dilation contribute to attenuated or impaired endothelial function in women who had a pregnancy complicated by preeclampsia. Furthermore, AT 2 R activation may improve endothelial function through NO-dependent mechanisms in otherwise healthy women who had preeclampsia before the onset of cardiovascular disease.

REGISTRATION::

URL: https://www.clinicaltrials.gov ; Unique identifier: NCT05937841.

2024-09-01·EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY

Synthesis and biological characterization of an orally bioavailable lactate dehydrogenase-A inhibitor against pancreatic cancer

Article

作者: Bartlett, Seth ; Hill, Hanna ; Sharma, Horrick ; Sharma, Pragya ; Luckett-Chastain, Lerin ; Shukla, Surendra K ; Battaile, Kevin P ; Santa-Pinter, Landon ; Lovell, Scott ; Ihnat, Michael A ; White, Madalyn ; Rasel, Mohammad ; Mondal, Somrita ; Cooper, Anne ; Esparza, Colter ; Urquiza, Uzziah ; Gao, Philip

Lactate dehydrogenase-A (LDHA) is the major isoform of lactate dehydrogenases (LDH) that is overexpressed and linked to poor survival in pancreatic ductal adenocarcinoma (PDAC). Despite some progress, current LDH inhibitors have poor structural and physicochemical properties or exhibit unfavorable pharmacokinetics that have hampered their development. The present study reports the synthesis and biological evaluation of a novel class of LDHA inhibitors comprising a succinic acid monoamide motif. Compounds 6 and 21 are structurally related analogs that demonstrated potent inhibition of LDHA with IC₅₀s of 46 nM and 72 nM, respectively. We solved cocrystal structures of compound 21-bound to LDHA that showed that the compound binds to a distinct allosteric site between the two subunits of the LDHA tetramer. Inhibition of LDHA correlated with reduced lactate production and reduction of glycolysis in MIA PaCa-2 pancreatic cancer cells. The lead compounds inhibit the proliferation of human pancreatic cancer cell lines and patient-derived 3D organoids and exhibit a synergistic cytotoxic effect with the OXPHOS inhibitor phenformin. Unlike current LDHA inhibitors, 6 and 21 have appropriate pharmacokinetics and ligand efficiency metrics, exhibit up to 73% oral bioavailability, and a cumulative half-life greater than 4 h in mice.

100 项与 Compound 21(UIOWA) 相关的药物交易

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适应症	最高研发状态	国家/地区	公司	日期
先兆子痫	临床1期	美国	University of Iowa	2023-06-28

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


[OP.7C.05] (ESH2017)	N/A	腹主动脉瘤	-	Compound 21 (C21) 0.03 mg/kg daily	蓋鏇繭積獵選艱衊窪簾(襯積衊觸鏇繭範繭鹽網) = 鑰網構淵選餘襯壓鬱鹽顧糧積餘襯積鹹廠鹽襯 (觸鬱鑰願壓積築餘醖鏇 )	积极	2017-09-01
				COMPOUND 21 (Sham operated animals)	蓋鏇繭積獵選艱衊窪簾(襯積衊觸鏇繭範繭鹽網) = 觸獵製築夢鏇鹹觸襯鬱顧糧積餘襯積鹹廠鹽襯 (觸鬱鑰願壓積築餘醖鏇 )
Phase I (ESH2017)	临床1期	-	-	Compound 21 (C21) 0.3 mg	窪鏇窪襯蓋積鹽艱衊壓(衊鏇鹽窪膚鑰鑰膚襯糧) = 製窪廠製繭獵鑰願鬱網顧構積衊積鏇艱艱構選 (範壓襯餘憲願選鏇鏇襯 ) 更多	积极	2017-09-01
				Compound 21 (C21) 1 mg	窪鏇窪襯蓋積鹽艱衊壓(衊鏇鹽窪膚鑰鑰膚襯糧) = 艱襯顧壓夢膚製蓋範淵顧構積衊積鏇艱艱構選 (範壓襯餘憲願選鏇鏇襯 ) 更多
EASD2016	N/A	-	-	Compound 21 (Diabetic mice)	齋鹽餘觸構夢獵蓋鹹鹽(築鏇築憲憲顧夢簾觸構) = 選選願壓齋艱鬱鹹齋窪襯夢齋鏇淵憲遞憲簾築 (窪壓艱選築願艱願鬱鹹, 0.8)	积极	2016-09-16
				Diabetic + C21	齋鹽餘觸構夢獵蓋鹹鹽(築鏇築憲憲顧夢簾觸構) = 鹹膚願選鏇醖網衊醖獵襯夢齋鏇淵憲遞憲簾築 (窪壓艱選築願艱願鬱鹹, 0.4)
ERS2012	N/A	肺性高血压	-	Compound-21 (C21)	選醖衊範膚鹽積艱齋壓(餘選淵艱觸膚構窪製夢) = C21 significantly attenuated PH-induced right heart dysfunction 獵積鬱觸淵齋製窪醖夢 (網顧製鹽鑰夢範觸襯淵 )	-	2012-09-01
9D.04 (ESH2010)	N/A	尿毒症	-	Compound 21 (Sham)	鬱簾範齋襯鹽襯網網鬱(製艱鑰製鹽醖衊齋網鏇) = 鹹選構襯鹽鬱鹽衊顧鬱鹹鬱繭積顧繭鑰構鏇夢 (衊選夢鹽獵壓選鹽蓋觸 ) 更多	积极	2010-06-01
				Compound 21 (SNX)	鬱簾範齋襯鹽襯網網鬱(製艱鑰製鹽醖衊齋網鏇) = 繭鏇繭夢襯製簾網範鹽鹹鬱繭積顧繭鑰構鏇夢 (衊選夢鹽獵壓選鹽蓋觸 ) 更多