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）

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

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.

2024-02-01·Bioorganic & Medicinal Chemistry

Development of a tetrahydroindazolone-based HDAC6 inhibitor with in-vivo anti-arthritic activity

Article

作者: Ha, Nina ; Bae, Daekwon ; Lee, Changsik ; Park, Hyun-Ju ; Yang, Hyun-Mo ; Nam, Gibeom ; Min, Jaeki

Histone deacetylase 6 (HDAC6) induces the expression of pro-inflammatory cytokines in macrophages; therefore, HDAC inhibitors may be beneficial for the treatment of macrophage-associated immune disorders and chronic inflammatory diseases, including atherosclerosis and rheumatoid arthritis. Structure-activity relationship studies were conducted on various phenyl hydroxamate HDAC6 inhibitors with indolone/indazolone-based bi- or tricyclic ring moieties as the cap group aiming to develop novel anti-arthritic drug candidates. Several compounds exhibited nanomolar activity and HDAC6 selectivity greater than 500-fold over HDAC1. Compound 21, a derivative with the tetrahydroindazolone cap group, is a potent HDAC6 inhibitor with an IC₅₀ of 18 nM and 217-fold selectivity over HDAC1 and showed favorable oral bioavailability in animals. Compound 21 increases the acetylation level of tubulin without affecting histone acetylation in cutaneous T-cell lymphoma cells and inhibits TNF-α secretion in LPS-stimulated macrophage cells. The anti-arthritic effects of compound 21 were evaluated using a rat adjuvant-induced arthritis (AIA) model. Treatment with compound 21 significantly reduced the arthritis score, and combination treatment with methotrexate showed a synergistic effect in AIA models. We identified a novel HDAC6 inhibitor, compound 21, with excellent in vivo anti-arthritic efficacy, which can lead to the development of oral anti-arthritic drugs.

2024-01-01·Psychopharmacology

Clozapine N-oxide, compound 21, and JHU37160 do not influence effortful reward-seeking behavior in mice

Article

作者: Ozawa, Takaaki ; Aomine, Yoshiatsu ; Macpherson, Tom ; Oyama, Yoshinobu ; Sakurai, Koki ; Hikida, Takatoshi

AbstractRationaleClozapine N-oxide (CNO) has been developed as a ligand to selectively activate designer receptors exclusively activated by designer drugs (DREADDs). However, previous studies have revealed that peripherally injected CNO is reverse-metabolized into clozapine, which, in addition to activating DREADDs, acts as an antagonist at various neurotransmitter receptors, suggesting potential off-target effects of CNO on animal physiology and behaviors. Recently, second-generation DREADD agonists compound 21 (C21) and JHU37160 (J60) have been developed, but their off-target effects are not fully understood.ObjectivesThe present studies assessed the effect of novel DREADD ligands on reward-seeking behavior.MethodsWe first tested the possible effect of acute i.p. injection of low-to-moderate (0.1, 0.3, 1, 3 mg/kg) of CNO, C21, and J60 on motivated reward-seeking behavior in wild-type mice. We then examined whether a high dose (10 mg/kg) of these drugs might be able to alter responding.ResultsLow-to-moderate doses of all drugs and a high dose of CNO or C21 did not alter operant lick responding for a reward under a progressive ratio schedule of reinforcement, in which the number of operant lick responses to obtain a reward increases after each reward collection. However, high-dose J60 resulted in a total lack of responding that was later observed in an open field arena to be due to a sedative effect.ConclusionsThis study provides definitive evidence that commonly used doses of CNO, C21, and J60 have negligible off-target effects on motivated reward-seeking but urges caution when using high doses of J60 due to sedative effects.

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	鏇築製餘製遞餘範鏇顧(築窪襯構餘顧築鹽襯選) = 製齋鑰構衊廠衊繭遞夢餘餘艱製遞遞衊構遞顧 (獵壓獵壓憲鏇廠齋糧製 )	积极	2017-09-01
				COMPOUND 21 (Sham operated animals)	鏇築製餘製遞餘範鏇顧(築窪襯構餘顧築鹽襯選) = 鏇餘齋觸鑰壓製網鏇窪餘餘艱製遞遞衊構遞顧 (獵壓獵壓憲鏇廠齋糧製 )
EASD2016	N/A	-	-	Compound 21 (Diabetic mice)	廠觸鬱構夢鏇鏇齋遞積(淵積齋艱鹹繭鬱蓋壓齋) = 襯遞鏇觸衊鑰糧餘網繭糧積顧艱鑰鏇憲簾淵簾 (簾齋製廠鑰選齋獵選鏇, 0.8)	积极	2016-09-16
				Diabetic + C21	廠觸鬱構夢鏇鏇齋遞積(淵積齋艱鹹繭鬱蓋壓齋) = 顧築鏇鬱觸壓蓋窪衊鹽糧積顧艱鑰鏇憲簾淵簾 (簾齋製廠鑰選齋獵選鏇, 0.4)
9D.04 (ESH2010)	N/A	尿毒症	-	Compound 21 (Sham)	膚鹽觸鹹積衊觸醖廠壓(鑰網壓製鑰構觸蓋齋製) = 膚觸鹹構積顧選壓遞淵襯積艱鹹廠醖簾壓築觸 (鏇糧簾鏇顧選糧觸範艱 ) 更多	积极	2010-06-01
				Compound 21 (SNX)	膚鹽觸鹹積衊觸醖廠壓(鑰網壓製鑰構觸蓋齋製) = 襯憲鏇鑰襯製觸選廠壓襯積艱鹹廠醖簾壓築觸 (鏇糧簾鏇顧選糧觸範艱 ) 更多