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Decades-old renin inhibitors are still struggling to find a niche in antihypertensive therapy. A fleeting look at the old and the promising new molecules
Hypertension is a diverse illness interlinked with cerebral, cardiovascular (CVS) and renal abnormalities. Presently, the malady is being treated by focusing on Renin- angiotensin system (RAS), voltage-gated calcium channels, peripheral vasodilators, renal and sympathetic nervous systems. Cardiovasc...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Elsevier Ltd.
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7112834/ https://www.ncbi.nlm.nih.gov/pubmed/32247750 http://dx.doi.org/10.1016/j.bmc.2020.115466 |
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author | Ramya, Krishnappa Suresh, Ramalingam Kumar, Honnavalli Yogish Kumar, B.R. Prashantha Murthy, N.B. Sridhara |
author_facet | Ramya, Krishnappa Suresh, Ramalingam Kumar, Honnavalli Yogish Kumar, B.R. Prashantha Murthy, N.B. Sridhara |
author_sort | Ramya, Krishnappa |
collection | PubMed |
description | Hypertension is a diverse illness interlinked with cerebral, cardiovascular (CVS) and renal abnormalities. Presently, the malady is being treated by focusing on Renin- angiotensin system (RAS), voltage-gated calcium channels, peripheral vasodilators, renal and sympathetic nervous systems. Cardiovascular and renal abnormalities are associated with the overactivation of RAS, which can be constrained by angiotensin- converting enzyme inhibitors (ACEIs), angiotensin II (Ang-II) -AT1 receptor blockers (ARBs) and renin inhibitors. The latter is a new player in the old system. The renin catalyzes the conversion of angiotensinogen to Angiotensin I (Ang-I). This can be overcome by inhibiting renin, a preliminary step, eventually hinders the occurrence of the cascade of events in the RAS. Various peptidomimetics, the first-generation renin inhibitors developed six decades ago have limited drug-like properties as they suffered from poor intestinal absorption, high liver first-pass metabolism and low oral bioavailability. The development of chemically diverse molecules from peptides to nonpeptides expanded the horizon to achieving direct renin inhibition. Aliskiren, a blockbuster drug that emerged as a clinical candidate and got approved by the US FDA in 2007 was developed by molecular modeling studies. Aliskiren indicated superior to average efficacy and with minor adverse effects relative to other RAS inhibitors. However, its therapeutic use is limited by poor oral bioavailability of less than 2% that is similar to first-generation peptidic compounds. In this review, we present the development of direct renin inhibitors (DRIs) from peptidic to nonpeptidics that lead to the birth of aliskiren, its place in the treatment of cardiovascular diseases and its limitations. |
format | Online Article Text |
id | pubmed-7112834 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Elsevier Ltd. |
record_format | MEDLINE/PubMed |
spelling | pubmed-71128342020-04-02 Decades-old renin inhibitors are still struggling to find a niche in antihypertensive therapy. A fleeting look at the old and the promising new molecules Ramya, Krishnappa Suresh, Ramalingam Kumar, Honnavalli Yogish Kumar, B.R. Prashantha Murthy, N.B. Sridhara Bioorg Med Chem Article Hypertension is a diverse illness interlinked with cerebral, cardiovascular (CVS) and renal abnormalities. Presently, the malady is being treated by focusing on Renin- angiotensin system (RAS), voltage-gated calcium channels, peripheral vasodilators, renal and sympathetic nervous systems. Cardiovascular and renal abnormalities are associated with the overactivation of RAS, which can be constrained by angiotensin- converting enzyme inhibitors (ACEIs), angiotensin II (Ang-II) -AT1 receptor blockers (ARBs) and renin inhibitors. The latter is a new player in the old system. The renin catalyzes the conversion of angiotensinogen to Angiotensin I (Ang-I). This can be overcome by inhibiting renin, a preliminary step, eventually hinders the occurrence of the cascade of events in the RAS. Various peptidomimetics, the first-generation renin inhibitors developed six decades ago have limited drug-like properties as they suffered from poor intestinal absorption, high liver first-pass metabolism and low oral bioavailability. The development of chemically diverse molecules from peptides to nonpeptides expanded the horizon to achieving direct renin inhibition. Aliskiren, a blockbuster drug that emerged as a clinical candidate and got approved by the US FDA in 2007 was developed by molecular modeling studies. Aliskiren indicated superior to average efficacy and with minor adverse effects relative to other RAS inhibitors. However, its therapeutic use is limited by poor oral bioavailability of less than 2% that is similar to first-generation peptidic compounds. In this review, we present the development of direct renin inhibitors (DRIs) from peptidic to nonpeptidics that lead to the birth of aliskiren, its place in the treatment of cardiovascular diseases and its limitations. Elsevier Ltd. 2020-05-15 2020-03-28 /pmc/articles/PMC7112834/ /pubmed/32247750 http://dx.doi.org/10.1016/j.bmc.2020.115466 Text en © 2020 Elsevier Ltd. All rights reserved. Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. |
spellingShingle | Article Ramya, Krishnappa Suresh, Ramalingam Kumar, Honnavalli Yogish Kumar, B.R. Prashantha Murthy, N.B. Sridhara Decades-old renin inhibitors are still struggling to find a niche in antihypertensive therapy. A fleeting look at the old and the promising new molecules |
title | Decades-old renin inhibitors are still struggling to find a niche in antihypertensive therapy. A fleeting look at the old and the promising new molecules |
title_full | Decades-old renin inhibitors are still struggling to find a niche in antihypertensive therapy. A fleeting look at the old and the promising new molecules |
title_fullStr | Decades-old renin inhibitors are still struggling to find a niche in antihypertensive therapy. A fleeting look at the old and the promising new molecules |
title_full_unstemmed | Decades-old renin inhibitors are still struggling to find a niche in antihypertensive therapy. A fleeting look at the old and the promising new molecules |
title_short | Decades-old renin inhibitors are still struggling to find a niche in antihypertensive therapy. A fleeting look at the old and the promising new molecules |
title_sort | decades-old renin inhibitors are still struggling to find a niche in antihypertensive therapy. a fleeting look at the old and the promising new molecules |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7112834/ https://www.ncbi.nlm.nih.gov/pubmed/32247750 http://dx.doi.org/10.1016/j.bmc.2020.115466 |
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