Endothelin Receptor Antagonists nyob rau hauv lub raum kab mob
Sep 21, 2023
Abstract:Endothelin (ET) tau pom tias muaj ntau ntxiv hauv cov kab mob hauv lub raum thib ob rau hyperglycemia, kub siab, acidosis, thiab muaj cov tshuaj insulin lossis proinflammatory cytokines. Hauv cov ntsiab lus no, ET, ntawm endothelin receptor hom A (ETA) ua kom muaj zog, ua rau muaj kev cuam tshuam vasoconstriction ntawm afferent arterioles uas ua rau cov teebmeem deleterious xws li hyperfiltration, podocyte puas, proteinuria thiab, thaum kawg, GFR poob. Yog li ntawd, endothelin receptor antagonists (ERAs) tau raug npaj los ua ib txoj hauv kev kho kom txo tau cov proteinuria thiab ua kom qeeb ntawm cov kab mob hauv lub raum. Cov pov thawj preclinical thiab kho mob tau qhia tias kev tswj hwm ntawm ERAs txo cov mob raum fibrosis, o thiab proteinuria. Tam sim no, kev ua tau zoo ntawm ntau ERAs los kho cov kab mob raum tau raug sim hauv cov kev sim tshuaj ntsuam xyuas randomized; Txawm li cas los xij, qee qhov ntawm cov no, xws li avosentan thiab atrasentan, tsis tau ua lag luam vim yog cov xwm txheej tsis zoo cuam tshuam nrog lawv siv. Yog li ntawd, txhawm rau ua kom zoo dua ntawm cov khoom tiv thaiv ntawm ERAs, kev siv ETA receptor-specific antagonists thiab/los yog muab lawv nrog sodium-glucose cotransporter 2 inhibitors (SGLT2i) tau raug npaj los tiv thaiv oedema, lub ntsiab ERAs cuam tshuam cov nyhuv deleterious. Kev siv dual angiotensin-II hom 1 / endothelin receptor blocker (spartan) kuj raug soj ntsuam los kho cov kab mob raum. Ntawm no, peb tau tshuaj xyuas lub ntsiab ERAs tsim thiab cov pov thawj preclinical thiab kev kho mob ntawm lawv lub raum-tiv thaiv cov teebmeem. Tsis tas li ntawd, peb tau muab cov ntsiab lus tseem ceeb ntawm cov tswv yim tshiab uas tau npaj los koom ua ke ERAs hauv kev kho mob raum.
Ntsiab lus: endothelin; endothelin receptor antagonists (ERAs); atrasentan; spartan; kab mob raum
1. Taw qhia: Endothelin System
Endothelin (ET) yog 21-aminoacid polypeptide piav raws li vasoconstrictor loj ntawm cov kab mob. Nws yog tsim los ntawm endothelial hlwb, tab sis kuj los ntawm cov hlwb ntawm lub raum system, xws li cov epithelial thiab mesangial hlwb [1]. Hickey et al. yog thawj zaug piav qhia txog qhov muaj nyob ntawm cov molecule uas muaj peev xwm ua rau capillary constriction tsim los ntawm endothelium hauv 1985 tab sis nws tsis yog txog 1988 uas ET tau txheeb xyuas [2,3]. ET polypeptide muaj nyob rau hauv peb isoforms: ET-1, ET-2, thiab ET-3, nrog ET-1 yog cov vasoconstrictor loj tshaj plaws thiab tsuas yog ib qho pom ntawm cov protein. qib hauv lub raum [4] ET-2 thiab ET-3 txawv ntawm ET-1 nyob rau hauv ob thiab tsib seem ntawm N-terminal kawg, raws li (Table 1), uas txiav txim siab qhov sib txawv ntawm receptor-binding affinity [ 5]. Ntxiv mus, ET-1 feem ntau yog tso tawm los ntawm cov hlwb endothelial, thaum txoj hnyuv thiab lub raum tsim ET-2 thiab cov ntaub so ntswg neural tso tawm ET-3; peb lub isoforms tuaj yeem ua hauv paracrine lossis autocrine yam [5].
Table 1. ET1, ET2 thiab ET3 amino acid sequences. ET yog ib qho 21-amino acid peptide muaj nyob rau hauv peb lub isoforms sib txawv hauv lub cev: ET-1, ET-2 thiab ET-3 [5]; qhov sib txawv ntawm cov amino acid ib ntus ntawm lawv yog qhia nyob rau hauv bold.
Qhov kev txiav txim ntawm ET yog channeled los ntawm ob daim nyias nyias G-protein coupled receptors: Endothelin receptor A (ETA) thiab B (ETB). ETA yog nyob rau hauv cov leeg nqaij leeg thiab nthuav tawm ntau qhov kev sib raug zoo rau ET-1 thiab ET-2 dua li rau ET-3, vim qhov sib txawv ntawm cov amino acid sequences (Table 1). ETA activation induces lub zog vasoconstrictor teb thiab txhawb nqa cell proliferation thiab tsub zuj zuj ntawm extracellular matrix. ETB muaj nyob rau hauv vascular du leeg hlwb thiab endothelial hlwb. Peb ET isoforms nthuav tawm tib qhov kev sib raug zoo rau ETB receptor, thiab nws qhov kev ua kom ua rau muaj kev tiv thaiv kab mob thiab tshuaj tiv thaiv kab mob, nrog rau kev tso tawm ntau yam vasodilator molecules [6]. Qee cov kws tshaj lij tau qhia txog kev nthuav dav ntxiv ntawm ET receptors, subdividing ETB rau ETB1 thiab ETB2 kom sib txawv cov receptors tam sim no ntawm cov hlwb endothelial thiab cov uas muaj nyob rau ntawm cov leeg nqaij pob txha, feem. Txawm li cas los xij, tsis muaj pov thawj pharmacological uas qhia tau hais tias qhov sib txawv ntawm cov receptors qhia los ntawm ob hom cell [7]. ET-1 khi rau ETA ua rau G-proteins thiab phospholipase C (PLC) koom nrog, ua rau inositol triphosphate (IP3) thiab diacylglycerol (DAG) tsim. Tom qab ntawd, IP3 activates tshwj xeeb endoplasmic reticulum receptors los txhawb kev tso tawm ntawm khaws cia Ca2+ ua rau muaj kev nce ceev hauv intracellular Ca2+, uas tso cai rau cell contraction thiab vasoconstriction tom qab. ET-1 kev ua los ntawm ETA receptors kuj tseem muaj lwm txoj hauv kev qhia, xws li phospholipase D (PLD) lossis mitogen-activated protein kinase (MAPK) txoj hauv kev, txhawm rau ua kom muaj lwm yam teebmeem ntawm lub cev xws li kev loj hlob ntawm tes lossis mitogenesis [5] . Contrarily, ETB receptors tsim lawv cov vasodilator teebmeem los ntawm kev ua kom cov nitric oxide synthases (NOS) system thiab tso tawm vasodilators li nitric oxide (NO) [8,9].
Nyob rau hauv lub raum, ET muaj lub luag haujlwm tseem ceeb hauv cov ntshav ntws thiab glomerular filtration tswj thiab hauv dej-sodium, thiab acid-base balances. ETA thiab ETB tau nthuav tawm ntawm glomerular podocytes, mesangial hlwb, thiab ntawm afferent thiab efferent arterioles. Hais txog lub tubular compartment, ETB yog qhia nyob rau hauv tag nrho cov cheeb tsam nyob rau hauv lub raum tubule thaum ETA yog scarcely qhia nyob rau hauv lub proximal tubule thiab descending Henle lub voj [10]. Nyob rau hauv physiological tej yam kev mob, ET-1 los ntawm ETA tsim vasoconstriction ntawm afferent arteriole, txo cov ntshav txaus thiab, yog li ntawd, glomerular filtration rate (GFR). Tsis tas li ntawd, kev ua kom ETB ua rau vasodilation, cov teebmeem tiv thaiv kab mob, thiab ET-1 depuration [8,9]. Hauv cov kab mob pathological, xws li ntshav qab zib lossis ntshav siab, qhov concentration ntawm ET-1 nce ntxiv vim yog hyperglycemia, acidosis, thiab muaj cov insulin, angiotensin II, thiab proinflammatory cytokines, uas ua rau vasoconstriction. Qhov no tuaj yeem ua rau muaj kev cuam tshuam loj heev xws li hyperfiltration (tsuas yog nyob rau hauv cov ntshav qab zib nephropathy thaum ntxov lossis cov kab mob hauv lub raum kev rog [11–13]) lossis podocyte puas thiab, thaum kawg, proteinuria thiab GFR poob (Daim duab 1) [14].
Cov endothelin receptor antagonists (ERA) yog postulated raws li kev kho mob lub tswv yim los txo cov proteinuria thiab ncua kev loj hlob ntawm GFR poob [14]. Cov txiaj ntsig tau cog lus siv ERAs hauv cov kab mob raum tau txais nyob rau xyoo tas los no. Lub hom phiaj ntawm qhov kev tshuaj xyuas no yog muab cov ntsiab lus ntawm ERAs tseem ceeb thiab cov txheej txheem los ntawm cov tshuaj no tiv thaiv lub raum nrog kev tsom tshwj xeeb rau cov txiaj ntsig tau txais hauv cov kev tshawb fawb tshiab thiab kev sim tshuaj ntsuam xyuas. Tsis tas li ntawd, peb muab kev saib xyuas ntawm cov txheej txheem tshiab tshiab los qhia ERAs rau kev tiv thaiv kab mob raum.
Daim duab 1. Cov txheej txheem ntawm endothelin system. ET-1 ua los ntawm nws txoj kev khi rau ETA thiab ETB ua rau muaj kev cuam tshuam rau hauv lub raum. Cov teebmeem tshwm sim los ntawm kev ua kom ETA tau pom hauv liab thiab cov teebmeem ntawm ETB ua kom pom yog xiav. Hauv cov kab mob pathological, hyperglycemia, acidosis thiab muaj cov tshuaj insulin, angiotensin II thiab proinflammatory cytokines ua rau nce ET-1 concentration, uas ua rau muaj kev cuam tshuam rau lub raum ua haujlwm, xws li vasoconstriction thiab endothelial puas tsuaj, o, fibrosis, podocyte. kev puas tsuaj los yog albuminuria.
2. Cov txheej txheem
Peb tau tshawb nrhiav PubMed, Scopus, thiab Google Academic thaum lub Kaum Ib Hlis-Lub Kaum Ob Hlis 2022 siv cov lus tshawb fawb hauv qab no (ib leeg ntawm kev sib koom ua ke) txhawm rau nrhiav cov ntawv tshaj tawm ntsig txog endothelin system thiab endothelin receptor antagonists hauv kev sim thiab tib neeg lub raum kab mob: "endothelin lossis ET", "endothelin receptor antagonists lossis ERA", "endothelin receptor A lossis ETA", "endothelin receptor B lossis ETB", "mob raum", "mob raum", "mob raum", "mob mob", "sim qauv", " nas, "rat", "podocytes", "randomized soj ntsuam sim". Peb tau tshuaj xyuas cov ntawv ceeb toom pom thiab xaiv cov kev tshawb fawb cuam tshuam los tsim cov ntawv tshuaj xyuas. Rau cov ntu "5. Preclinical trials pov thawj ntawm ERAs tiv thaiv cov teebmeem ntawm lub raum puas" thiab "6. Randomized controlled trials (RCTs) siv ERAs rau kev tiv thaiv kab mob raum kev loj hlob", peb tsuas yog tsom rau cov hauj lwm luam tawm nyob rau hauv tsib lub xyoos dhau los tsis los sib tshooj yav dhau los tshuaj xyuas ntawm lub ncauj lus. Lub tswv yim tshuaj xyuas cov ntaub ntawv tiav yog muaj los ntawm cov kws sau ntawv raws li kev thov. Tsis tas li ntawd, peb tau sab laj https://clinicaltrials.gov thaum lub Kaum Ib Hlis-Lub Kaum Ob Hlis 2022 kom tau txais cov ntaub ntawv hais txog cov kev sim tshuaj tsis tu ncua uas peb tau pib siv tus lej sib thooj National Clinical Trial (NCT) tus lej.
3. Cov Endothelin Receptor Antagonists
Endothelin receptor antagonists (ERAs) yog cov tshuaj uas thaiv cov endothelin receptors, tiv thaiv kev ua haujlwm ntawm endothelin. Muaj ntau hom ERAs, uas tuaj yeem paub qhov txawv ntawm lawv txoj kev sib raug zoo rau kev khi rau ETA lossis ETB. Qee zaum, cov antagonists no tsis tuaj yeem xaiv thiab muaj peev xwm cuam tshuam nrog ob qho tib si receptors. Qhov kev xaiv ntawm ERA rau txhua hom receptor subtype yog txiav txim siab los ntawm kev sib tw sib tw sib tw tiv thaiv [125I]-ET-1 uas tso cai rau kev suav qhov sib npaug ntawm qhov sib npaug ntawm txhua qhov sib xyaw rau ob qho tib si receptors, ETA, thiab ETB. Txhawm rau tsim qhov kev xaiv xaiv, hauv 2006, Maguire thiab Davenport li al. [15] tau hais tias ERA yuav tsum nthuav tawm ntau dua 100-fold selectivity rau ETA lossis ETB los txiav txim siab xaiv rau ib lossis lwm qhov receptor. Cov uas muaj tsawg dua 100-fold selectivity yuav tsum tau muab faib ua cov tsis xaiv los yog sib xyaw antagonists [15]. Lub ntsiab ERAs tau sau tseg hauv Table 2.
Feem ntau ntawm cov antagonists ntawm no tau piav qhia tseem tab tom tshawb nrhiav hauv kev sim tshuaj tsis tu ncua, thaum lwm tus tsis siv hauv kev kho mob vim tias tsis muaj txiaj ntsig lossis vim muaj cov xwm txheej tsis zoo cuam tshuam txog lawv kev siv uas cuam tshuam kev nyab xeeb ntawm cov neeg mob. Yog li, txhawm rau ua kom zoo dua ntawm cov tebchaw no nrog cov txiaj ntsig zoo (Table 2), cov kev kho mob raws li kev tshawb fawb yog kev sib xyaw ntawm ERAs nrog rau lwm cov tshuaj nephroprotective xws li sodium-glucose cotransporter 2 inhibitors (SGLT2i) thiab kev siv cov tshuaj dual xws li sparsentan. uas thaiv tib lub sijhawm angiotensin-II hom 1 thiab endothelin receptors.
3.1. ETA-Selective Receptor Antagonists
Kev khi ntawm ET -1 rau ETA, nyob rau hauv cov kab mob pathologic, tuaj yeem ua rau vasoconstriction, o, cellular raug mob, fibrosis, thiab, thaum kawg mus rau proteinuria thiab poob ntawm lub raum ua haujlwm [31]. Txhawm rau tiv thaiv cov teebmeem no, ob peb xaiv ETA-receptor antagonists tau tsim los ua cov tshuaj kho tau zoo. Qee tus ntawm lawv tam sim no tau siv los kho cov kab mob pulmonary arterial hypertension (ambrisentan thiab macitentan), lub sijhawm no, lwm tus tseem tab tom kawm hauv kev tshawb fawb soj ntsuam tsis tu ncua. Txog niaj hnub no, tsis muaj ib qho ntawm ETA-xaiv receptor antagonists tau pom zoo los kho cov kab mob raum, txawm tias lawv tau pom tias muaj kev tiv thaiv raum (Table 2).
BQ-123 yog thawj ETA xaiv antagonist peptide cais tawm uas tau los ntawm Strep tomyces misakiensis fermentation khoom. Nws tau raug siv hauv kev tshawb nrhiav hauv ob qho tib si tsiaj thiab tib neeg qhov twg cov molecule txo glomerular permeability [20]. Darusentan (LU 135252) yog ib qho kev xaiv endothelin receptor antagonist, nrog siab affinity ntawm ETA receptor [17], nrog ib tug piv ntawm cov txheeb ze selectivity ntawm 170: 1 ETA: ETB [32]. Nws yog muab los ntawm kev ua kom zoo dua ntawm ob qho kev coj ua thawj zaug (LU 110896 thiab LU 110897) pom nyob rau hauv kev tshuaj ntsuam ntawm lub tsev qiv ntawv ntawm tib neeg recombinant ETA receptors [33]. Darusentan tau cog lus tias yuav ua rau txo cov ntshav siab hauv cov neeg mob ntshav siab hauv cov kev tshawb fawb thaum ntxov tab sis hmoov tsis ua tiav kev ua tau zoo hauv theem III kev tshawb fawb soj ntsuam [32]. Lwm cov piv txwv ntawm ETA xaiv antagonists yog sitaxentan, ambrisentan, avosentan, atrasentan, macitentan thiab zibotentan (Table 2). Tam sim no, sitaxentan, ambrisentan thiab macitentan tau txais kev pom zoo los kho pulmonary arterial hypertension [21,34,35] thaum avosentan, atrasentan thiab zibotentan tau npaj ua cov tshuaj kho mob raum mob [19,24,36]. Macitentan yog ib qho sulfamide nrog siab affinity rau ETA uas tau siv nyob rau hauv pulmonary arterial hypertension txij li thaum nws pom zoo nyob rau hauv 2013 [37,38]. Nws belongs rau tiam tom ntej ntawm antagonists, raws li nws tau tsim raws li lub hauv paus ntawm bosentan [20], tab sis nrog kev txhim kho xws li ib tug ntev receptor binding muaj peev xwm thiab zoo dua pharmacodynamics thiab pharmacokinetics [37,38]. Hauv vivo, macitentan yog metabolized los ntawm cytochrome P450 3A4 (CYP3A4) rau hauv cov metabolite nquag, uas yog hu ua aprocitentan (ib qho tsis xaiv ERA, saib hauv qab) [26]. Avosentan yog ib qho kev xaiv ETA inhibitor uas nthuav tawm ~500-fold selectivity rau ETA tshaj ETB receptors [39]. Nws tau tsim los rau kev kho mob ntshav qab zib nephropathy. Kev tshawb fawb ua los ntawm Wenzel et al. Hauv 2009 [23] tau qhia tias qhov sib ntxiv ntawm avosentan rau tus qauv ntawm kev kho mob ntshav siab nrog RAS blockers ua rau muaj kev cuam tshuam ntxiv rau cov neeg mob ntshav qab zib nephropathy. Txawm li cas los xij, txoj kev tshawb fawb thib ob los ntsuas kev kho mob mus sij hawm ntev nrog avosentan raug tso tseg ntxov vim muaj kev txhawj xeeb txog kev nyab xeeb [36]. Atrasentan yog qhov ncauj xaiv ETA inhibitor nrog xaiv ETA: ETB blockade piv ntawm 1200: 1 [40] thiab 1800-fold selectivity rau ETA [39]. Hauv cov neeg mob ntshav qab zib thiab mob raum mob ntev, atrasentan txo qhov kev pheej hmoo ntawm lub raum cov xwm txheej thiab albuminuria [19,22,41]. Tam sim no, nws tab tom kawm nyob rau theem 2 kev soj ntsuam txuas ntxiv los ntsuas qhov ua tau zoo thiab kev nyab xeeb ntawm atrasentan hauv cov neeg mob uas muaj cov kab mob glomerular protein (AFFINITY: Atrasen tan hauv Cov Neeg Mob Proteinuric Glomerular Diseases-NCT04573920). Thaum kawg, zibotentan yog ib qho kev xaiv ETA antagonist, uas qhia tau hais tias muaj zog affinity rau qhov tshwj xeeb receptor [42]. Hauv kev sim tshuaj ntsuam xyuas tsis ntev los no, nws tau pom tias zibotentan tuaj yeem muaj txiaj ntsig zoo rau kev kho mob ntawm cov kab mob sclerosis cuam tshuam nrog rau mob raum vim tias nws cov teebmeem hauv kev txhim kho ntawm kwv yees GFR thiab tsis tuaj yeem nce qib endothelin serum thaum kho [24].
3.2. ETB-Selective Receptor Antagonists
Ob peb ETB-xaiv antagonists tau tsim. Qhov no tuaj yeem piav qhia los ntawm qhov tseeb tias thaum endothelin khi ETB, nws ua rau muaj txiaj ntsig zoo xws li vasodilation; Yog li inhibiting qhov kev txiav txim ntawm ETB tej zaum yuav tsis yog ib qho kev kho mob zoo. Tsis tas li ntawd, ETB-xaiv antagonists feem ntau tsis muaj zog dua li ETA-xaiv agonists [20]. Txawm li cas los xij, qee qhov me me tau tsim los thaiv ETB, xws li tsis yog peptide RO468443 uas qhia 2000-fold ETB xaiv [43], thiab A192621 [20]. Txawm li cas los xij, qhov tseem ceeb tshaj plaws ETB-xaiv antagonist yog BQ-788, uas tau piav qhia thawj zaug los ntawm Ishikawa li al. xyoo 1994. BQ-788 tau kawm ua ke nrog BQ-123, ETA-xaiv ERA, thiab nws ua rau txo qis glomerular permeability rau albumin tab sis tsis ntxiv rau cov nyhuv BQ{{16 }} hauv monotherapy [39]. Hauv kev mob qog noj ntshav, BQ-788 inhibits cell loj hlob thiab induces kev tuag ntawm melanoma hlwb, ob qho tib si hauv vivo thiab hauv vitro [26].
3.3. Non-Selective Endothelin Receptor Antagonists
Qee ERAs tuaj yeem cuam tshuam nrog ETA lossis ETB receptors. Qee qhov tsis xaiv ERAs yog bosentan, tezosentan thiab aprocitentan. Bosentan yog ib qho non-peptide derivative dual endothelin receptor antagonist nrog affinity rau ob qho tib si receptors ETA thiab ETB, tab sis nrog NW nyuam qhuav siab dua affinity rau ETA (ETA: ETB 20: 1) [22,35,40]. Tam sim no, nws yog siv nyob rau hauv kev kho mob ntawm pulmonary arterial hypertension [34] thiab nyob rau hauv pediatric idiopathic pulmonary hypertension [22]. Bosentan txo qis vascular tsis kam, ua rau lub plawv dhia ntau ntxiv yam tsis cuam tshuam lub plawv dhia. Nws kuj tseem ua lub luag haujlwm hauv inhibition ntawm endothelial cell proliferation [25]. Tezosentan yog dual endothelin receptor antagonist nrog kev xaiv ntawm 30: 1 ETA: ETB [44]. Nws tau tsim los rau kev kho mob plawv tsis ua hauj lwm thiab kev tshawb fawb preclinical tau pom tias bosentan txhim kho hemodynamics thiab lub raum ua haujlwm hauv nas [26] tab sis tsis txhim kho dyspnoea lossis txo qhov kev pheej hmoo ntawm cov xwm txheej hauv plawv [26]. Aprociten tan (ACT{15}}) yog ib qho inhibitor dual ntawm ETA / ETB nrog qhov sib piv ntawm 1:16 [45–47]. Nws yog nyob rau hauv chav kawm sulfonamide ntawm molecules thiab tau los ntawm oxidative depropylation los ntawm macitentan [45-47]. Hauv kev sim tshuaj PRECISION, ua tiav hauv 2022, aprocitentan txo qis ntshav siab hauv cov neeg mob uas tiv taus kub siab [27].
3.4. Lwm Hom Endothelin Receptor Antagonists
Spartan (BMS{0}}) yog dual endothelin receptor/angiotensin-II hom 1 receptor antagonist (DEARA) uas nthuav tawm siab affinity rau ETA (~1000-fold). Nws tau tsim los ntawm kev sib txuas cov qauv ntawm ob qho tib si irbesartan, angiotensin II type 1 receptor antagonist, thiab biphenyl sulfonamide, endothelin receptor antagonist. Yog li, sparsentan blocks tib lub sijhawm RAS thiab endothelin system yog vim li cas nws thiaj li yuav tsum tau qhia cov teebmeem kev tiv thaiv ntxiv. Sparsentan txo cov ntshav siab hauv cov neeg mob ntshav siab [28]. Lub antiproteinuric thiab muaj peev xwm nephroprotective teebmeem ntawm spartan yog tam sim no kawm nyob rau hauv focal segmental glomerulosclerosis (DUPLEX txoj kev tshawb no) [29] thiab IgA Nephropathy (PROTECT txoj kev tshawb no; NCT03762850) cov neeg mob nyob rau hauv ib tug tsis tu ncua theem 3 kev soj ntsuam kev sim.
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