{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T09:09:26Z","timestamp":1788772166081,"version":"build-2803163510"},"reference-count":128,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T00:00:00Z","timestamp":1788739200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Life"],"abstract":"<jats:p>Resistant hypertension (RH) is a high-risk phenotype associated with increased cardiovascular and renal morbidity despite multidrug therapy. Dysregulation of the renin\u2013angiotensin\u2013aldosterone system (RAAS), particularly excess aldosterone activity, plays a central role in the pathophysiology of RH. Although conventional RAAS-targeted therapies including angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and mineralocorticoid receptor antagonists improve outcomes, their effectiveness is limited by aldosterone breakthrough, persistent non-genomic aldosterone effects, hyperkalaemia, and off-target adverse effects. Aldosterone synthase inhibitors (ASIs) have emerged as a novel therapeutic strategy targeting CYP11B2, the terminal enzyme responsible for aldosterone biosynthesis. This review summarises the physiological basis of aldosterone synthesis, the pathological consequences of aldosterone excess, and the pharmacological evolution of ASIs. Early-generation agents were limited by inadequate selectivity between CYP11B2 and the closely related CYP11B1 enzyme, resulting in cortisol suppression and deoxycorticosterone accumulation. Advances in structural biology and medicinal chemistry enabled the development of second-generation ASIs with markedly improved selectivity and preserved cortisol biosynthesis. Recent clinical trials of baxdrostat, lorundrostat, vicadrostat, and dexfadrostat have demonstrated clinically meaningful reductions in blood pressure and albuminuria with acceptable safety profiles. Based on the positive trial data, baxdrostat has become the first in class ASI to be approved by regulatory authorities for management of uncontrolled hypertension.<\/jats:p>","DOI":"10.3390\/life16091495","type":"journal-article","created":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T08:07:06Z","timestamp":1788768426000},"page":"1495","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Aldosterone Synthase Inhibitors: Emerging Therapeutic Strategies in Resistant Hypertension"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2360-7580","authenticated-orcid":false,"given":"Akshyaya","family":"Pradhan","sequence":"first","affiliation":[{"name":"Department of Cardiology, King George\u2019s Medical University, Shahmina Road, Chowk, Lucknow 226003, Uttar Pradesh, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Monika","family":"Bhandari","sequence":"additional","affiliation":[{"name":"Department of Cardiology, King George\u2019s Medical University, Shahmina Road, Chowk, Lucknow 226003, Uttar Pradesh, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abhishek","family":"Singh","sequence":"additional","affiliation":[{"name":"Department of Cardiology, King George\u2019s Medical University, Shahmina Road, Chowk, Lucknow 226003, Uttar Pradesh, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pravesh","family":"Vishwakarma","sequence":"additional","affiliation":[{"name":"Department of Cardiology, King George\u2019s Medical University, Shahmina Road, Chowk, Lucknow 226003, Uttar Pradesh, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9378-6505","authenticated-orcid":false,"given":"Kunal","family":"Mahajan","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Himachal Heart Institute, Mandi 175021, Himachal Pradesh, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0511-2621","authenticated-orcid":false,"given":"Marco Alfonso","family":"Perrone","sequence":"additional","affiliation":[{"name":"Division of Cardiology and CardioLab, Department of Clinical Sciences and Translational Medicine, University of Rome Tor Vergata, 00133 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7606-5826","authenticated-orcid":false,"given":"Akash","family":"Batta","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Dayanand Medical College and Hospital, Ludhiana 141001, Punjab, India"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e53","DOI":"10.1161\/HYP.0000000000000084","article-title":"Resistant hypertension: Detection, evaluation, and management: A scientific statement from the American Heart Association","volume":"72","author":"Carey","year":"2018","journal-title":"Hypertension"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"957","DOI":"10.1016\/S0140-6736(21)01330-1","article-title":"Worldwide trends in hypertension prevalence and progress in treatment and control from 1990 to 2019: A pooled analysis of 1201 population-representative studies with 104 million participants","volume":"398","author":"Zhou","year":"2021","journal-title":"Lancet"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1136\/heartjnl-2018-313599","article-title":"Global prevalence of resistant hypertension: A meta-analysis of data from 3.2 million patients","volume":"105","author":"Noubiap","year":"2019","journal-title":"Heart"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"S1","DOI":"10.1016\/j.kint.2020.11.003","article-title":"KDIGO 2021 clinical practice guideline for the management of blood pressure in chronic kidney disease","volume":"99","author":"Cheung","year":"2021","journal-title":"Kidney Int."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1635","DOI":"10.1161\/CIRCULATIONAHA.111.068064","article-title":"Incidence and prognosis of resistant hypertension in hypertensive patients","volume":"125","author":"Daugherty","year":"2012","journal-title":"Circulation"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1002\/ejhf.2333","article-title":"2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: Developed by the Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). 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