Aldosterone synthase, polymorphism of its CYP11B2 gene in arterial hypertension and cardiovascular diseases associated with it (literature review)

D.K. Miloslavsky, S.N. Koval, I.A. Snegurskaya, V.V. Bozhko, E.N. Shchenyavskaya

Abstract


The article presents the data of foreign and national literature on the pathogenetic role of aldosterone (AL), levels of aldosterone synthase (AS) and gene polymorphisms of this enzyme in patients with various forms of arterial hypertension, associated with diseases of the heart and vessels, such as hypertrophic cardiomyopathy, atrial fibrillation, brain pathology etc. The activation of circulating and local renin-angiotensin system results in increased secretion of the powerful vasoconstrictor angiotensin II, which stimulates AL production in an auto- and paracrine way. Angiotensin II and AL have independent regulatory effect on the function and structure of the heart and blood vessels, kidneys and brain. Both hormones stimulate hypertrophy of cardiomyocytes and vascular smooth muscle cells, hyperplasia of myocardial fibroblasts, synthesis of connective tissue matrix. As a result, the left ventricular hypertrophy is formed, cardiac remodeling is progressing, in which processes AL is involved. The main humoral, metabolic, cellular, immune-inflammatory and profibrogenic effects of aldosterone are considered. The AS gene CYP11B2 catalyzes the last stage of the synthesis of AL from desoxycorticosterone. The gene is located in the g21 region of chromosome 8, and consists of nine exons and eight introns. Single nucleotide polymorphisms are known in the promoter region of AL and in the AS gene. The polymorphism of the 5th section of this gene, which manifests itself by replacing cytosine (C) with thymine (T) at the 344th position of the 344 T/C nucleotide sequence, rs1799998, has been most fully investigated. MiR-766 can be used to suppress the expression of the AS gene in an experiment, as well as in humans, and reduce blood pressure level in people having the –344T allele. The determination of the single nucleotide replacement of T by C at position 344 of the CYP11B2 gene is carried out by polymerase chain reaction with polymorphism of the length of restriction fragment analysis. Currently, a list of forward and reverse primers, which are used in the amplification of the CYP11B2 gene, has been compiled. In the number of studies, the relationship between AS gene polymorphism and risk factors of cardiovascular and endocrine pathology were studied, the sex, gender and ethnic characteristics of AS gene polymorphism were considered, and the results of population studies of gene polymorphism of AS in several European and Asian countries were received. The information is provided on the AS levels and gene polymorphisms of this enzyme in arterial hypertension, including its resistant form, in the combination of ischemic heart disease, postinfarction cardiosclerosis, their participation in cardiovascular remodeling, the formation of left ventricular hypertrophy, in hypertensive nephropathy, cerebral stroke, heart failu­re. The levels of AL and gene polymorphism of AS also can be used as differential diagnostic criteria for hypertension with low plasma renin activity, with renovascular and resistant hypertension, at hyperaldosteronism types 1 and 2, aldosteromas, apparent mineralocorticoid excess syndrome, congenital adrenal hyperplasia. The congenital defects of enzymatic activity of AS, insufficiency of AS and aldosteronism (arterial hypertension), which are cured by glucocorticoids, are described. The results of several studies provide conflicting data on the degree of response to antihypertensive therapy by various first-line drugs and mineralocorticoid receptor antagonists, depending on the haplotype CYP11B2, are presented. The prospects of therapeutic use of a new class of drugs — aldosterone synthase inhibitors among various categories of patients with symptoms of arterial hypertension are considered.

Keywords


arterial hypertension; associated cardiovascular diseases; aldosterone; aldosterone synthase levels; aldosterone synthase gene polymorphisms; differential diagnostic use; thera­peutic use of aldosterone synthase inhibitors; review

References


Sun X, Yang J, Hou X, Li J, Shi Y, Jing Y. Relationship between -344T/C polymorphism in the aldosterone synthase gene and atrial fibrillation in patients with essential hypertension. J Renin Angiotensin Aldosterone Syst. 2011 Dec;12(4): 557-63.

Sun XJ, Liu SR, Zhang CH, Yuan GH, Chen HY, Hou XF. [Association of aldosterone synthase gene -344 T/C polymorphism with early renal damage in Han nationality with essential hypertension]. Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 2007 Apr;24(2): 153-6. Chinese.

Vamsi UM, Swapna N, Padma G, Vishnupriya S, Padma T. Haplotype association and synergistic effect of human aldosterone synthase (CYP11B2) gene polymorphisms causing susceptibility to essential hypertension in Indian patients. Clin Exp Hypertens. 2016;38(8): 659-665.

Wang L, Zhang B, Li M., et al. Association between single-nucleotide polymorphisms in six hypertensive candidate genes and hypertension among northern Han Chinese individuals. Hypertens Res. 2014 Dec;37(12): 1068-74. doi: 10.1038/hr.2014.124.

Sia SK, Chiou HL, Chen SC, Tsai CF, Yang SF, Ueng KC. Distribution and phenotypic expression of mineralocorticoid receptor and CYP11B2 T-344C polymorphisms in a Taiwanese hypertensive population. Mol Biol Re. 2013 May;40(5): 3705-11.

Whaley-Connell A, Johnson MS, Sowers JR. Aldosterone: role in the cardiometabolic syndrome and resistant hypertension. Prog. Cardiovasc. Dis. 2010; 52: 401–409

Garg R. Aldosterone and the Mineralocorticoid Receptor: Risk Factors for Cardiometabolic Disorders / Garg R, Adler GK. // Curr Hypertens Rep.- 2015.- Vol.17(7).- P.52. doi: 10.1007/s11906-015-0567-8.

Ruhs S, Nolze A, Hübschmann R, Grossmann C. 30 YEARS OF THE MINERALOCORTICOID RECEPTOR: Nongenomic effects via the mineralocorticoid receptor. // J Endocrinol. 2017 Jul; 234(1):T107-T124. doi: 10.1530/JOE-16-0659. Epub 2017 Mar 27. Review.

Schütten MT. The Link Between Adipose Tissue Renin-Angiotensin-Aldosterone System Signaling and Obesity-Associated Hypertension / Schütten MT, Houben AJ, de Leeuw PW, Stehouwer CD. // Physiology (Bethesda). -2017.- Vol. 32(3).- P.197-209. doi: 10.1152/physiol.00037.2016.

Kawarazaki W, Fujita T. The Role of Aldosterone in Obesity-Related Hypertension.// Am J Hypertens. 2016 Apr;29(4):415-23. doi: 10.1093/ajh/hpw003. Epub 2016 Feb 28. Review.

Hall JE, do Carmo JM, da Silva AA, Wang Z, Hall ME. Obesity-induced hypertension: interaction of neurohumoral and renal mechanisms.// Circ Res. 2015 Mar 13;116(6):991-1006. doi: 10.1161/CIRCRESAHA.116.305697. Review.

Underwood PC, Adler GK. The renin angiotensin aldosterone system and insulin resistance in humans.// Curr Hypertens Rep. 2013 Feb;15(1):59-70. doi: 10.1007/s11906-012-0323-2. Review.

Alvarez-Madrazo S. Common polymorphisms in the CYP11B1 and CYP11B2 genes: evidence for a digenic influence on hypertension / Alvarez-Madrazo S, Mackenzie SM, Davies E. [et al.] // Hypertension. -2013.- Vol.61(1). - Р.232-9.

MacKenzie S.M. Analysis of the Aldosterone Synthase (CYP11B2) and 11β-Hydroxylase (CYP11B1) Genes / MacKenzie S.M., Davies E., Alvarez-Madrazo S. // Methods Mol Biol.- 2017.- Vol.1527.- P.139-150. doi: 10.1007/978-1-4939-6625-7-11.

Nejatizadeh A, Kumar R, Stobdan T. [et al.] CYP11B2 gene haplotypes independently and in concurrence with aldosterone and aldosterone to renin ratio increase the risk of hypertension / Nejatizadeh A, Kumar R, Stobdan T. [et al.] // Clin Biochem.- 2010.- Vol.43(1-2).- Р.136-41.

Newton-Cheh C. Clinical and genetic correlates of aldosterone -to-renin ratio and relations to blood pressure in a community sample / Newton-Cheh C., Guo C.Y., Gona P. [et al.] // Hypertens. – 2007. – Vol. 49. – P. 846–856.

Maharjan S. Human aldosterone synthase gene polymorphism promotes miRNA binding and regulates gene expression / Maharjan S, Mopidevi B, Kaw MK. [et al.] // Physiol Genomics. -2014.- Vol.46(24). - Р.860-5.

Ye WJ, Zheng L, Wang ZH, Chen HH. [Meta analysis on the association of CYP11B2 gene polymorphism and essential hypertension in Chinese Han population]. Zhonghua Xin Xue Guan Bing Za Zhi. 2013 Sep;41(9): 795-9. Chinese.

Niu WQ, Guo SJ, Zhang Y, Gao PJ, Zhu DL. Genetic and functional analyses of aldosterone synthase gene C-344T polymorphism with essential hypertension. J Hum Hypertens. 2010 Jun;24(6): 427-9.

Pan XQ, Liu YY, Wang LF, Liu YJ, Zhang YH, Qiu CC, Tong WJ. [Association of aldosterone synthase (CYP11B2) gene -344T/C polymorphism with essential hypertension in Mongolian nationality]. Zhonghua Yu Fang Yi Xue Za Zhi. 2010 Sep;44(9): 800-5. Chinese.

Pan XQ, Liu YY, Zhang XY, Zhang YH, Xu Q, Qiu CC, Tong WJ. [Impact of gene-environment interaction between the C (-344) T polymorphism of CYP11B2 and drinking index on the risk of hypertension under multifactor dimensionality reduction model in Chinese Mongolian population]. Zhonghua Liu Xing Bing Xue Za Zhi. 2009 Sep;30(9): 955-9. Chinese.

Pan XQ, Zhang YH, Liu YY, Tong WJ. Interaction between the C(-344)T polymorphism of CYP11B2 and alcohol consumption on the risk of essential hypertension in a Chinese Mongolian population. Eur J Epidemiol. 2010 Nov;25(11): 813-21.

Song Y, Miyaki K, Araki J, Zhang L, Takahashi Y, Nakayama T, Muramatsu M. Influence of CYP11B2 gene polymorphism on the prevalence of hypertension and the blood pressure in Japanese men: interaction with dietary salt intake. J Nutrigenet Nutrigenomics. 2008;1(5): 252-8.

Blacher J, Kakou A, Lacombe JM, Safar ME. Preferential association of aldosterone synthase gene polymorphism with central blood pressure and wave reflections in hypertensive individuals. J Hum Hypertens. 2010 Apr;24(4): 291-9.

Byrd JB, Auchus RJ, White PC. Aldosterone Synthase Promoter Polymorphism and Cardiovascular Phenotypes in a Large, Multiethnic Population-Based Study. J Investig Med. 2015 Oct;63(7): 862-6. doi: 10.1097/JIM.0000000000000220

Chen B, Nie S, Luo S, Zhang W, Xiao C. Association of the human CYP11B2 gene and essential hypertension in southwest Han Chinese population: a haplotype-based case-control study. Clin Exp Hypertens. 2011;33(2): 106-12. doi: 10.3109/10641963.2010.531835. 

Cheng X, Xu G. A systemic review of the relationship between aldosterone synthase - 344 C/T polymorphism and hypertension in Han. Clin Exp Hypertens. 2010;32(5): 301-7.

Chou CH, Ueng KC, Yang SF, Wu CH, Wang PH. Relationship of Genetic Polymorphisms of Aldosterone Synthase Gene Cytochrome P450 11B2 and Mineralocorticoid Receptors with Coronary Artery Disease in Taiwan. Int J Med Sci. 2016 Feb 1;13(2): 117-23.

Li W, Liu C. The -344C/T polymorphism in the CYP11B2 gene is associated with essential hypertension in the Chinese. J Renin Angiotensin Aldosterone Syst. 2014 Jun;15(2): 150-5.

Li X, Xie P, He J., et al. CYP11B2 gene polymorphism and essential hypertension among Tibetan, Dongxiang and Han populations from northwest of China. Clin Exp Hypertens. 2016;38(4): 375-80.

Rajan S, Ramu P, Umamaheswaran G, Adithan C. Association of aldosterone synthase (CYP11B2 C-344T) gene polymorphism & susceptibility to essential hypertension in a south Indian Tamil population. Indian J Med Res. 2010 Oct;132: 379-85.

Hlubocká Z, Jáchymová M, Heller S., et al. Association of the -344T/C aldosterone synthase gene variant with essential hypertension. Physiol Res. 2009;58(6): 785-92.

Gurov EV, Topchieva LV, Kolomeychuk SN, Malyisheva IE, Korneva VA. Rol polimorfnogo markYora -344T/C gena aldosteronsintazyi v geneticheskoy predraspolozhennosti zhiteley Karelii k serdechno-sosudistyim zabolevaniyam. Meditsinskaya genetika. 2011; 5(107)  (in Russian).

Gamra Hamad Dweihi Al-Qahtani. Prevalence of Aldosterone Synthase GenePolymorphisms in Saudi Hypertensive Patients. In Partial Fulfillment of the Requirement for the Master’s Degree in Pharmacology at The Department of Pharmacology College of Pharmacy King Saud University, 2009: p.52.

Russo P, Loguercio M, Lauria F., et al. European Collaborative Group of the IMMIDIET Project. Age- and gender-dependent association of the -344C/T polymorphism of CYP11B2 with blood pressure in European populations. J Hum Hypertens. 2007 Apr;21(4): 333-6.

Pavlova OS, Ogurtsova SE, Liventseva MM, Kovsh EV, Afonin VYu, Mrochek AG. Polimorfizm S(-344)T gena aldosteronsintazyi i essentsialnaya arterialnaya gipertenziya. Evraziyskiy kardiologicheskiy zhurnal. 2016; 4: 42-47. (in Russian).

Patnaik M, Pati P, Swain SN, Mohapatra MK, Dwibedi B, Kar SK, Ranjit M. Aldosterone synthase C-344T, angiotensin II type 1 receptor A1166C and 11-β hydroxysteroid dehydrogenase G534A gene polymorphisms and essential hypertension in the population of Odisha, India. J Genet. 2014 Dec;93(3): 799-808.

Dolzhenko MM, Lobach LE, Potashev SV. Vpliv polImorfIzmu gena aldosteronsintazi (CYP11B2) na sertsevo-sudinnu sistemu. Ukrainian cardiology journal. 2015; 5: 104-109. (in Russian).

Sookoian S. Role of the C-344T aldosterone synthase gene variant in left ventricular mass and left ventricular structure-related phenotypes / Sookoian S, Gianotti TF, Pirola CJ. // Heart.- 2008.- Vol.94(7).- Р.903-10.

Kurbanova D. Genetic background of left ventricular hypertrophy in Uzbek hypertensive men / Kurbanova D, Eliseyeva M. // Turk Kardiyol Dern Ars. -2010.- Vol.38(7).- Р.466-72.

Khamidullaeva GA. [Specifics of distribution of polymorphic markers of the renin-angiotensin-system genes, relation to ventricular hypertrophy in patients with essential hypertension of Uzbek nationality] / Khamidullaeva GA, Eliseeva MR, Srozhiddinova NZ, Abdullaeva GZh. // Kardiologiia. -2007.- Vol.47(4).- Р.54-8.

Wang L, Zhou J, Zhang B., et al. Association of echocardiographic left ventricular structure and -344C/T aldosterone synthase gene variant: A meta-analysis. J Renin Angiotensin Aldosterone Syst. 2015 Dec;16(4): 858-71. doi: 10.1177/1470320314535459. 

Yahontov DA, Derisheva DA, Gulyaeva LF. Polimorfizm gena aldosteronsintazyi u bolnyih arterialnoy gipertenziey v sochetanii s ishemicheskoy boleznyu serdtsa pri razlichnoy masse miokarda levogo zheludochka. Sistemnyie gipertenzii. 2014;11(1): 16-20. (in Russian).

Derisheva DA. Porazhenie koronarnogo rusla i polimorfizm gena aldosteronsintazyi u bolnyih ishemicheskoy boleznyu serdtsa v sochetanii s arterialnoy gipertenziey pri razlichnoy masse miokarda levogo zheludochka. Vrach-Aspirant. 2013; 61(6.2): 312-319  (in Russian).

Tykhonova SA. Analiz klinichnykh, henetychnykh i hendernykh determinant neefektyvnoho likuvannya v patsiyentiv z arterial'noyu hipertenziyeyu. Arterial'na hipertenziya. 2016; 2: 98-100.

Lacchini R, Sabha M, Coeli FB., et al. T allele of -344 C/T polymorphism in aldosterone synthase gene is not associated with resistant hypertension. Hypertens Res. 2009 Feb;32(2): 159-62. doi: 10.1038/hr.2008.36. 

Baird TE, Palmer BR, Frampton CM, Yandle TG, Skelton L, Richards AM, Cameron VA. Association of the aldosterone synthase gene C-344T polymorphism with risk factors and survival in a post-myocardial infarction cohort . J Hum Hypertens. 2007 Mar;21(3): 256-8

Normaznah Y, Azizah MR, Kuak SH, Rosli MA. CYP11B2 gene polymorphism among coronary heart disease patients and blood donors in Malaysia. Malays J Pathol. 2015 Apr;37(1): 45-7.

Boduła A, Dołyk A, Protasiewicz J, Adamiec R. [The role of the -344C/T polymorphism of the aldosterone synthase gene (CYP11B2) in cardiovascular diseases]. Postepy Hig Med Dosw (Online). 2007 Dec 27;61: 838-47. Polish.

Cao FF, Chen XD, Wang QS, Li L, Wang XF, Lu M, Jin L. [Associations of the genetic polymorphisms in CYP11B2 gene with nonfamilial structural atrial fibrillation]. Zhonghua Liu Xing Bing Xue Za Zhi. 2009 Oct;30(10): 1069-72. Chinese.

Fu X, Ma X, Zhong L, Song Z. Relationship between CYP11B2-344T>C polymorphsim and atrial fibrillation: A meta-analysis. J Renin Angiotensin Aldosterone Syst. 2015 Mar;16(1): 185-8.

Huang M, Gai X, Yang X., et al. Functional polymorphisms in ACE and CYP11B2 genes and atrial fibrillation in patients with hypertensive heart disease. Clin Chem Lab Med. 2009;47(1): 32-7. doi: 10.1515/CCLM.2009.023.

Yatskevich ES, Snezhitskiy VA. Assotsiatsiya polimorfizma - S/344T gena aldosteronsintazyi (CYP11B2) s gipertrofiey levogo zheludochka i urovnem aldosteronsintazyi plazmyi u patsientov s neklapannoy fibrillyatsiey predserdiy. Meditsinskiy zhurnal. 2015; 2: 118-123. (in Russian).

Yatskevich ES. Vzaimosvyaz strukturno-funktsionalnogo remodelirovaniya predserdiy s urovnem gomotsisteina, prolina, glitsina i polimorfizmom -S344/T gena aldosteronsintazyi u patsientov s fibrillyatsiey predserdiy. Available from:  http://lib.grid.by/handle/123456789/55112 (in Russian).

Karabaeva AZh, Essaian AM, Kayukov IG. Association of aldesterone synthase gene polymorphism with concentration of plasma aldosterone, arterial hypertension and myocardium remodeling in program dialysis patients. Nefrologiya. 2007;11(3): 48-52. (in Russian).

Bantis C, Heering PJ, Stangou M., et al. Influence of aldosterone synthase gene C-344T polymorphism on focal segmental glomerulosclerosis. Nephrology (Carlton). 2011 Nov;16(8): 730-5.

Saidi S, Mahjoub T, Almawi WY. Aldosterone synthase gene (CYP11B2) promoter polymorphism as a risk factor for ischaemic stroke in Tunisian Arabs. J Renin Angiotensin Aldosterone Syst. 2010 Sep;11(3):180-6.

Yan G, Wang Y. Association of CYP11B2 gene polymorphism with ischemic stroke in the north Chinese Han population. Neurol India. 2012 Sep-Oct;60(5): 504-9.

Munshi A, Sharma V, Kaul S., et al. Association of the -344C/T aldosterone synthase (CYP11B2) gene variant with hypertension and stroke. J Neurol Sci. 2010 Sep 15;296(1-2):34-8. doi: 10.1016/j.jns.2010.06.013.

Srivastava S, Bhagi S, Kumari B, Chandra K, Sarkar S, Ashraf MZ. Association of polymorphisms in angiotensin and aldosterone synthase genes of the renin-angiotensin-aldosterone system with high-altitude pulmonary edema. J Renin Angiotensin Aldosterone Syst. 2012 Mar;13(1): 155-60. doi: 10.1177/1470320311430990. 

Ji X, Qi H, Li DB, Liu RK, Zheng Y, Chen HL, Guo JC. Associations between human aldosterone synthase CYP11B2 (-344T/C) gene polymorphism and antihypertensive response to valsartan in Chinese patients with essential hypertension. Int J Clin Exp Med. 2015 Jan 15;8(1): 1173-7.

Yu H, Lin S, Zhang Y, Liu G. Intron-2 conversion polymorphism of the aldosterone synthase gene and the antihypertensive response to angiotensin-converting enzyme inhibitors. J Hypertens. 2008 Feb;26(2): 251-6.

Fontana V, de Faria AP, Barbaro NR, Sabbatini AR, Modolo R, Lacchini R, Moreno H. Modulation of aldosterone levels by -344 C/T CYP11B2 polymorphism and spironolactone use in resistant hypertension. J Am Soc Hypertens. 2014 Mar;8(3):146-51.

Komissarova SM, Chakova NN, Niyazova SS., et al. Primenenie lozartana i ego kombinatsii so spironolaktonom u patsientov s gipertroficheskoy kardiomiopatiey i vliyanie polimorfizma gena aldosteronsintazyi na effektivnost kombinirovannoy terapii. Kardiologiya v Belarussii. 2014; 2: 139-150. (in Russian).

Li Y, Zhou Y, Yang P, Niu JQ, Wu Y, Zhao DD, Wu SL. Interaction of ACE and CYP11B2 genes on blood pressure response to hydrochlorothiazide in Han Chinese hypertensive patients. Clin Exp Hypertens. 2011;33(3): 141-6.

Adam O, Zimmer C, Hanke N, Hartmann RW, Klemmer B, Böhm M, Laufs U. Inhibition of aldosterone synthase (CYP11B2) by torasemide prevents atrial fibrosis and atrial fibrillation in mice. J Mol Cell Cardiol. 2015 Aug;85: 140-50.

Kobalava ZhD, Kotovskaya YuV, Villevalde SV, Amirbegishvili IM, Soloveva AE. Perspektivyi lecheniya arterialnoy gipertonii. Arterialnaya gipertenziya. 2013; 19(4): 280-28 (in Russian).

Oparil S, Schmieder RE. New approaches in the treatment of hypertension. Circ Res. 2015 Mar 13;116(6): 1074-95.

Andersen K. Aldosterone synthase inhibition in hypertension. Curr Hypertens Rep. 2013 Oct;15(5): 484-8. doi: 10.1007/s11906-013-0379-7.

Martin RE, Lehmann J, Alzieu T., et al. Synthesis of annulated pyridines as inhibitors of aldosterone synthase (CYP11B2). Org Biomol Chem. 2016 Jul 7;14(25): 5922-7.

Namsolleck P, Unger T. Aldosterone synthase inhibitors in cardiovascular and renal diseases. Nephrol Dial Transplant. 2014 Feb;29 Suppl 1: i62-i68. doi: 10.1093/ndt/gft402.

Blass B. Aldosterone synthase inhibitors. ACS Med Chem Lett. 2013 Mar 15;4(4): 375-6.

Cerny MA. Progress towards clinically useful aldosterone synthase inhibitors. Curr Top Med Chem. 2013;13(12): 1385-401.

Gromotowicz-Poplawska A, Szoka P, Kolodziejczyk P, Kramkowski K, Wojewodzka-Zelezniakowicz M, Chabielska E. New agents modulating the renin-angiotensin-aldosterone system-Will there be a new therapeutic option? Exp Biol Med (Maywood). 2016 Nov;241(17):1888-1899

Hargovan M, Ferro A. Aldosterone synthase inhibitors in hypertension: current status and future possibilities. JRSM Cardiovasc Dis. 2014 Feb 5;3:2048004014522440.  doi: 10.1177/2048004014522440.

Hoyt SB, Taylor J, London C., et al. Discovery of indazole aldosterone synthase (CYP11B2) inhibitors as potential treatments for hypertension. Bioorg Med Chem Lett. 2017 Jun 1;27(11): 2384-2388. doi: 10.1016/j.bmcl.2017.04.021.

Hu Q, Yin L, Ali A., et al. Novel pyridyl substituted 4,5-dihydro-[1,2,4]triazolo[4,3-a]quinolines as potent and selective aldosterone synthase inhibitors with improved in vitro metabolic stability. J Med Chem. 2015 Mar 12;58(5): 2530-7.

Petrilli WL, Hoyt SB, London C., et al. Discovery of Spirocyclic Aldosterone Synthase Inhibitors as Potential Treatments for Resistant Hypertension. ACS Med Chem Lett. 2016 Nov 22;8(1): 128-132.  doi: 10.1021/acsmedchemlett.6b00455.

Schumacher CD, Steele RE, Brunner HR. Aldosterone synthase inhibition for the treatment of hypertension and the derived mechanistic requirements for a new therapeutic strategy. J Hypertens. 2013 Oct;31(10): 2085-93.

Whitehead BR, Lo MM, Ali A., et al. Imidazopyridyl compounds as aldosterone synthase inhibitors. Bioorg Med Chem Lett. 2017 Jan 15;27(2): 143-146.




DOI: https://doi.org/10.22141/2224-1485.4.54.2017.109541

Refbacks

  • There are currently no refbacks.


Copyright (c) 2017 HYPERTENSION

Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 International License.

 

© Publishing House Zaslavsky, 1997-2018

 

   Seo анализ сайта