A series of renin inhibitors containing the dipeptide transition state mimics (2S,4S,5S)-5-amino-4-hydroxy-2-isopropyl-7-methyloctanoic acid (Leu (OH)/Val) and (2S,4S,5S)-5-amino-4-hydroxy-2-isopropyl-6-cyclohexylhexanoic acid (CHa /(OH)/Val) was prepared. A structure-activity study with Boc-Phe-His-Leu (OH)/Val-Ile-His-NH2 (8a) as starting material led to N-[(2S)-2-[(tert-butylsulfonyl)methyl]-3-phenylpropionyl]-His-Cha (OH)/ Val- NHC4H9-n (8i) which has the length of a tetrapeptide and contains only one natural amino acid. Compound 8i had an IC50 of 2 x 10(-9) M against human renin and showed high enzyme specificity; IC50 values against the related aspartic proteinases pepsin and cathepsin D were (8 x 10(-6) and 3 x 10(-6) M, respectively). In salt-depleted marmosets, 8i inhibited plasma renin activity PRA and lowered blood pressure for up to 2 h after oral administration of a dose of 10 mg/kg.
Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.1021/jm00117a027 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Novel Therapies for Right Ventricular Failure.
Curr Cardiol Rep
January 2025
Pediatric Advanced Heart Failure and Heart Transplant Program, University of Mississippi Medical Center, 2500 N State Street, Jackson, MS, USA.
Purpose Of Review: Traditionally viewed as a passive player in circulation, the right ventricle (RV) has become a pivotal force in hemodynamics. RV failure (RVF) is a recognized complication of primary cardiac and pulmonary vascular disorders and is associated with a poor prognosis. Unlike treatments for left ventricular failure (LVF), strategies such as adrenoceptor signaling inhibition and renin-angiotensin system modulation have shown limited success in RVF.
View Article and Find Full Text PDFExploring Neurohormonal Modulation by Acetazolamide in Heart Failure.
Cureus
December 2024
Gastroenterolgy, Sindh Institute of Urology and Transplantation, Karachi, PAK.
Background Heart failure (HF) is commonly managed by addressing water and sodium (Na) balance, with arterial circulation playing a major role in influencing renal Na and water excretion. Recently, chloride (Cl) has been recognized as an important factor in HF, associated with volume regulation and its modulation of renin-angiotensin-aldosterone system (RAAS) activity through macula densa signaling, which impacts Na retention and neurohormonal activation. Acetazolamide, a carbonic anhydrase inhibitor, can enhance decongestion in HF by increasing urinary Na and Cl excretion when added to loop diuretics, a mechanism supported by prior studies demonstrating improved urine output and decongestion.
View Article and Find Full Text PDFAdverse drug reactions and events in an Ageing PopulaTion risk Prediction (ADAPTiP) tool: the development and validation of a model for predicting adverse drug reactions and events in older patients.
Eur Geriatr Med
January 2025
Data Science Centre, School of Population Health, RCSI University of Medicine and Health Science, Lower Mercer Street, Dublin 2, Ireland.
Purpose: Older people are at an increased risk of developing adverse drug reactions (ADR) and adverse drug events (ADE). This study aimed to develop and validate a risk prediction model (ADAPTiP) for ADR/ADE in older populations.
Methods: We used the adverse drug reactions in an Ageing PopulaTion (ADAPT) cohort (N = 798; 361 ADR-related admissions; 437 non-ADR-related admissions), a cross-sectional study designed to examine the prevalence and risk factors for ADR-related hospital admissions in patients aged ≥ 65 years.
Phosphoproteomics for studying signaling pathways evoked by hormones of the renin-angiotensin system: A source of untapped potential.
Acta Physiol (Oxf)
February 2025
Department of Molecular Medicine, Cardiovascular and Renal Research Unit, University of Southern Denmark, Odense M, Denmark.
The Renin-Angiotensin System (RAS) is a complex neuroendocrine system consisting of a single precursor protein, angiotensinogen (AGT), which is processed into various peptide hormones, including the angiotensins [Ang I, Ang II, Ang III, Ang IV, Ang-(1-9), Ang-(1-7), Ang-(1-5), etc] and Alamandine-related peptides [Ang A, Alamandine, Ala-(1-5)], through intricate enzymatic pathways. Functionally, the RAS is divided into two axes with opposing effects: the classical axis, primarily consisting of Ang II acting through the AT receptor (ATR), and in contrast the protective axis, which includes the receptors Mas, ATR and MrgD and their respective ligands. A key area of RAS research is to gain a better understanding how signaling cascades elicited by these receptors lead to either "classical" or "protective" effects, as imbalances between the two axes can contribute to disease.
View Article and Find Full Text PDFApproach to Endocrine Hypertension: A Case-Based Discussion.
Curr Hypertens Rep
January 2025
Department of Endocrinology, Kasturba Medical College, Manipal Academy of Higher Education, Manipal, 576104, India.
Purpose Of Review: Hypertension remains a major chronic disease morbidity across the world, even in the twenty-first century, affecting ≈40% of the global population, adversely impacting the healthcare budgets in managing the high incidence of cardiovascular disease (CVD) complications and mortality because of elevated blood pressure (BP). However, evaluation and management of endocrine hypertension are not optimal in clinical practice. With three unique clinical case scenarios, we update the evidence base for diagnostic evaluation and management of endocrine hypertension in this review to inform appropriate day-to-day clinical practice decisions.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!