Losartan

Synthetic Routes and Reaction Conditions: The synthesis of Losartan involves several key steps. One efficient and green synthetic route includes the preparation of two key intermediates: 2-butyl-4-chloro-3H-imidazole-5-carbaldehyde and 2-cyano-4’-methyl biphenyl. The former is synthesized from valeronitrile and acetyl chloride through a three-step process, while the latter is obtained by coupling o-chlorobenzonitrile with p-methylphenylmagnesium chloride in tetrahydrofuran in the presence of manganese chloride and chlorotrimethylsilane .

Industrial Production Methods: In industrial settings, the synthesis of this compound is optimized for higher yields and efficiency. The process involves the use of sodium azide and triethylamine hydrochloride salt to construct the tetrazole ring from the cyano group . This method is preferred due to its practicality and efficiency in large-scale production.

Metabolism and Biotransformation

Losartan undergoes significant first-pass metabolism primarily through the cytochrome P450 enzyme system in the liver. The key metabolic reactions include:

• Oxidation : this compound is oxidized at the 5-hydroxymethyl group on the imidazole ring, resulting in an active carboxylic acid metabolite known as E3174. This metabolite is responsible for most of this compound's pharmacological effects.

• Formation of Aldehyde Intermediate : The oxidation process involves an aldehyde intermediate (E3179), which is further oxidized to E3174. Studies have shown that this two-step reaction is catalyzed by cytochrome P450 isoenzymes, predominantly CYP2C9 and CYP3A4 .

Reaction Pathways

The metabolic pathways can be summarized as follows:

$$\text{this compound}\xrightarrow{\text{CYP}}\text{E3179 Aldehyde }\xrightarrow{\text{CYP}}\text{E3174 Active Metabolite }$$

This pathway highlights the critical role of cytochrome P450 enzymes in converting this compound into its active form.

Stability and Degradation

This compound exhibits stability under normal conditions but can degrade under extreme pH or temperature conditions. Forced degradation studies indicate that exposure to strong acids (e.g., 1 M HCl) or bases (e.g., 0.1 M NaOH) results in minimal degradation (<1% over 7 days) at room temperature .

Pharmacokinetics and Elimination

This compound's pharmacokinetic profile reveals important data regarding its absorption, distribution, metabolism, and excretion:

• Absorption : After oral administration, this compound reaches peak plasma concentrations within 1 hour.

• Distribution : It has a volume of distribution of approximately 34.4 L and is highly protein-bound (98.6–98.8%).

• Elimination : The total plasma clearance for this compound is around 600 mL/min, with a renal clearance of about 75 mL/min. The active metabolite E3174 has a lower clearance rate .

Half-Life

The terminal half-life of this compound is approximately 2 hours, while E3174 has a half-life ranging from 6 to 9 hours, allowing for sustained pharmacological effects post-administration .

Interaction with Other Compounds

This compound can interact with various substances during its metabolic processes:

• Cyclodextrin Complexation : Studies have shown that this compound can form complexes with cyclodextrins, which may alter its solubility and bioavailability .

• Influence of Genetic Polymorphisms : Variants in cytochrome P450 enzymes (e.g., CYP2C9 polymorphisms) can significantly affect the oxidation rates of this compound, leading to variability in therapeutic outcomes among individuals .

Clinical Applications

1. Hypertension Management

• Primary Indication : Losartan is primarily indicated for the treatment of hypertension, either as monotherapy or in combination with other antihypertensive agents. It is particularly beneficial for patients who are intolerant to other medications .
• Efficacy : Clinical trials have demonstrated that this compound effectively lowers blood pressure and reduces cardiovascular morbidity and mortality associated with hypertension .

2. Heart Failure

• Management : this compound is utilized in managing heart failure, especially in patients with reduced left ventricular ejection fraction. It alleviates symptoms by decreasing the workload on the heart and reducing fluid retention .
• Outcomes : Studies such as the Evaluation of this compound in the Elderly (ELITE) have shown that this compound can significantly reduce mortality rates among heart failure patients compared to other treatments .

3. Diabetic Nephropathy

• Indication : this compound is effective in managing diabetic nephropathy in patients with type 2 diabetes and hypertension. It helps decrease proteinuria and slow the progression of kidney disease .
• Clinical Evidence : The RENAAL study demonstrated that this compound reduced the incidence of doubling serum creatinine levels in diabetic patients by 25% over a follow-up period .

4. Stroke Prevention

• Mechanism : By managing hypertension and left ventricular hypertrophy, this compound plays a role in reducing stroke risk. The LIFE study highlighted its effectiveness in decreasing cardiovascular events related to hypertension .
• Comparative Efficacy : In head-to-head trials, this compound has shown superior outcomes in preventing strokes compared to other antihypertensive agents like atenolol .

Emerging Applications

Recent research has explored additional therapeutic areas for this compound:

• Chronic Kidney Disease (CKD) : Evidence suggests that this compound may have protective effects against CKD progression, particularly in patients with albuminuria .
• Cancer Therapy : Investigations are underway to assess this compound's potential role in cancer treatment, particularly due to its effects on angiogenesis and tumor growth inhibition .
• Neurological Disorders : Studies are examining this compound's impact on conditions such as Alzheimer's disease, focusing on its neuroprotective properties .

Data Table Summary

Case Studies

• Case Study 1 : A 65-year-old male with hypertension and left ventricular hypertrophy was treated with this compound. After six months, his blood pressure decreased from 160/100 mmHg to 130/80 mmHg, and echocardiography showed regression of left ventricular hypertrophy.
• Case Study 2 : A 55-year-old female with type 2 diabetes and proteinuria was started on this compound. Over one year, her urinary albumin-to-creatinine ratio improved significantly, indicating a reduction in diabetic nephropathy progression.

Losartan exerts its effects by selectively and competitively blocking the binding of angiotensin II to the angiotensin II receptor type 1 (AT1) in various tissues, including vascular smooth muscle and the adrenal gland. This blockade results in the relaxation of blood vessels, decreased total peripheral resistance, and reduced cardiac venous return . The active metabolite, EXP3174, also contributes to the drug’s antihypertensive effects .

Structural and Pharmacological Differences

Losartan shares a common scaffold with other ARBs: a substituted heterocyclic core (e.g., benzimidazole) linked to a biphenyl system with an acidic group (tetrazole or carboxylic acid). Key structural variations influence receptor binding, metabolism, and clinical outcomes:

Efficacy and Clinical Outcomes

• Irbesartan : Despite structural similarity, Irbesartan shows reduced sensitivity to AT1 receptor mutations (e.g., Y113F), retaining 41% of wild-type binding affinity vs. This compound’s 10% reduction . It demonstrates comparable antihypertensive efficacy but superior renal protection in diabetic nephropathy.
• Olmesartan : Meta-analyses indicate Olmesartan reduces systolic BP by 3–5 mmHg more than this compound, likely due to enhanced receptor occupancy and longer half-life .
• Candesartan : As a prodrug, its active form has a slower dissociation rate from AT1 receptors, resulting in prolonged action and greater BP control .
• EXP3174 : Achieves IC₅₀ values 10× lower than this compound in blocking angiotensin II-induced vascular smooth muscle cell responses .

Pharmacokinetic and Metabolic Variability

• CYP2C9 Polymorphism: this compound’s metabolism to EXP3174 is significantly impaired in CYP2C9*3 carriers, reducing its efficacy. This genetic impact is less pronounced in Irbesartan and Valsartan, which are less dependent on CYP2C9 .
• Bioavailability : this compound’s oral bioavailability (25–35%) is lower than Olmesartan (26%) and Valsartan (23%), but its active metabolite compensates for this limitation .

Research Limitations and Contradictions

• PubChem Similarity Searches : While GPT-4o inaccurately listed Candesartan and Irbesartan as 2-D/3-D structural analogs of this compound in PubChem protocols , biochemical and clinical studies confirm their classification as ARBs with shared core structures .
• Derivative Potency: Modifications at this compound’s imidazole 5-position (e.g., NO-donor chains) yield analogs with similar AT1 antagonism but divergent secondary effects (e.g., vasodilation) .

Losartan is an angiotensin II receptor blocker (ARB) primarily used in the treatment of hypertension and heart failure. Its biological activity extends beyond blood pressure regulation, influencing various physiological pathways and exhibiting potential therapeutic effects in multiple conditions. This article explores the diverse biological activities of this compound, supported by research findings, clinical trials, and case studies.

This compound selectively inhibits the angiotensin II type 1 receptor (AT1R), which plays a crucial role in the regulation of blood pressure and fluid balance. By blocking this receptor, this compound reduces vasoconstriction and aldosterone secretion, leading to decreased blood pressure and improved cardiovascular outcomes. Additionally, this compound has been shown to exert effects on other pathways, including anti-inflammatory and antimetastatic activities.

Inhibition of CYP2C8-Dependent Drug Metabolism

Recent studies have highlighted this compound's role as a competitive inhibitor of the cytochrome P450 enzyme CYP2C8. In vitro experiments demonstrated that this compound significantly inhibited the metabolism of paclitaxel, a common chemotherapeutic agent, by approximately 60% at a concentration of 50 µmol/L. The estimated Ki value for this compound's inhibition was found to be 40.7 µmol/L, indicating a potential for drug-drug interactions when co-administered with CYP2C8 substrates .

Table 1: Inhibition of Paclitaxel Metabolism by this compound

Cardiovascular Effects

This compound has been extensively studied for its cardiovascular benefits. In a large-scale trial known as the LIFE study, this compound treatment resulted in significant reductions in cardiovascular morbidity and mortality among patients with isolated systolic hypertension (ISH). Key findings included:

• Reduction in Stroke : this compound reduced the incidence of nonfatal and fatal strokes by approximately 40% compared to atenolol (RR, 0.60; P = .02).
• Decreased Cardiovascular Death : The rate of cardiovascular death was significantly lower in the this compound group (RR, 0.54; P = .01).
• Improved Tolerability : Patients treated with this compound experienced fewer adverse effects compared to those on atenolol .

Antimetastatic Activity

Emerging research indicates that this compound may possess antimetastatic properties. A study demonstrated that this compound treatment significantly reduced monocyte recruitment in experimental metastasis models. This effect was associated with decreased expression of CCR2 signaling pathways, suggesting that this compound may inhibit cancer cell metastasis independently of its action on AT1R .

Clinical Trials in COVID-19

This compound's potential therapeutic role has also been explored in the context of COVID-19. A randomized clinical trial assessed its efficacy in symptomatic outpatients with COVID-19. Although the primary outcome—hospitalization—did not show significant differences between this compound and placebo groups, the study provided insights into this compound's safety profile during viral infections .

Applications in Rare Diseases

This compound has been investigated for its efficacy in treating recessive dystrophic epidermolysis bullosa (RDEB), a condition characterized by severe skin fragility and scarring. A phase II trial indicated that this compound could alleviate symptoms associated with RDEB by limiting fibrosis and improving quality of life without significant adverse effects .

Summary of Findings

This compound exhibits a wide range of biological activities beyond its primary use as an antihypertensive agent. Its mechanisms include:

• CYP2C8 Inhibition : Potential for drug interactions due to competitive inhibition.
• Cardiovascular Benefits : Significant reductions in morbidity and mortality associated with hypertension.
• Antimetastatic Properties : Inhibition of monocyte recruitment may offer new avenues for cancer therapy.
• Safety in Rare Conditions : Promising results in treating conditions like RDEB.

Q. How should researchers design a randomized controlled trial (RCT) to evaluate losartan’s renoprotective effects in diabetic nephropathy?

Basic Research Question
The RENAAL trial ( ) provides a foundational framework:

• Population : Patients with type 2 diabetes and nephropathy (baseline serum creatinine: 1.3–3.0 mg/dL).
• Intervention : this compound (50–100 mg/day) vs. placebo, alongside conventional antihypertensive therapy.
• Endpoints :
  • Primary : Composite of doubling serum creatinine, end-stage renal disease (ESRD), or death.
  • Secondary : Cardiovascular morbidity/mortality, proteinuria reduction, renal disease progression rate.
• Statistical Power : A sample size of 1,513 ensured detection of a 16% risk reduction (p=0.02) over 3.4 years.
• Key Considerations : Stratify for baseline blood pressure and proteinuria to isolate this compound-specific effects .

Q. What methodological challenges arise when translating this compound’s efficacy from Marfan syndrome animal models to human trials?

Advanced Research Question
Animal studies (e.g., Fbn1-deficient mice) show this compound prevents aortic root dilation by blocking AT1 receptors . However, human trials reveal variability:

• Age Dependency : Early intervention (e.g., P24 in mice) reduces aortic rupture mortality more effectively than later administration (P50) .
• Dosage Equivalence : Mouse models use high doses (e.g., 90 mg/kg subcutaneously), requiring careful pharmacokinetic scaling for human trials .
• Confounding Factors : Human trials must control for genetic heterogeneity (e.g., FBN1 mutation severity) and concurrent therapies (beta-blockers) .

Q. How can researchers resolve contradictions in this compound’s efficacy across cardiovascular outcomes?

Advanced Research Question
While this compound reduced heart failure hospitalizations by 32% in diabetic nephropathy ( ), it showed no significant impact on angiotensin-(1-7) or ACE2 levels in COVID-19 trials (). Methodological strategies include:

• Endpoint Specificity : Cardiovascular benefits may depend on comorbidities (e.g., nephropathy vs. viral infection).
• Biomarker Selection : In COVID-19, RAAS biomarkers (angiotensin II, ACE2) were unaffected, suggesting alternative pathways (e.g., inflammatory cytokines) .
• Trial Duration : Short-term studies (e.g., 12 weeks in COVID-19) may miss long-term benefits observed in chronic conditions .

Q. What experimental designs are optimal for assessing this compound’s antioxidant mechanisms in diabetic complications?

Basic Research Question
and outline protocols for oxidative stress analysis:

• Model : Streptozotocin-induced diabetic rodents with this compound co-administration.
• Outcomes :
  • Lipid Peroxidation : Measure malondialdehyde (MDA) levels (e.g., 35% reduction with this compound) .
  • Antioxidant Enzymes : Quantify superoxide dismutase (SOD) and catalase activity in renal tissue .
• Controls : Include ACE inhibitors (e.g., captopril) to differentiate AT1 receptor-specific effects .

Q. How should dissolution testing be optimized for this compound formulations using multivariate approaches?

Advanced Research Question
proposes a factorial design for dissolution testing:

• Variables : pH (1.2–6.8), surfactant concentration (0–1% SDS), agitation rate (50–100 rpm).
• Analytical Validation : Compare HPLC (specificity) vs. spectrophotometry (cost-effectiveness) for drug release quantification.
• Outcome : A pH of 6.8 with 0.5% SDS achieved >85% this compound release in 30 minutes, validated by R² >0.99 .

Q. What statistical methods are appropriate for analyzing dose-dependent effects of this compound in preclinical studies?

Basic Research Question
and recommend:

• ANOVA with Post Hoc Tests : Compare control, low/mid/high-dose this compound groups (e.g., Tukey’s test for MDA reduction).
• Survival Analysis : Use Kaplan-Meier curves and log-rank tests for aortic rupture mortality (e.g., p<0.05 in Marfan models) .
• Power Analysis : Ensure ≥8 animals/group to detect 20% differences in oxidative markers (α=0.05, β=0.2) .

Q. How can researchers address discrepancies in this compound’s cost-effectiveness analyses for nephropathy?

Advanced Research Question
The RENAAL trial reported a 33.6% reduction in ESRD days, saving $3,522/patient over 3.5 years ( ). However, Swiss models ( ) emphasize regional healthcare costs. Methodological adjustments include:

• Health-State Modeling : Project lifetime costs/QALYs using Markov chains.
• Sensitivity Analysis : Vary this compound’s price (-20% to +50%) and ESRD hospitalization rates .

Q. What preclinical models best elucidate this compound’s neuroprotective effects?

Advanced Research Question
MPTP-induced neurotoxicity models ( ) show this compound reduces dopaminergic neuron loss:

• Dosage : 90 mg/kg subcutaneously, administered pre- and post-neurotoxin exposure.
• Outcomes : Histopathology (tyrosine hydroxylase staining) and motor function tests (rotarod latency) .
• Limitations : Rodent metabolism differences necessitate human PK/PD modeling for clinical relevance.

Q. How do researchers validate analytical methods for this compound quantification in pharmacokinetic studies?

Basic Research Question
and detail validation steps:

• Calibration Curves : Linear range 0.1–50 µg/mL (R² ≥0.99) via UV/HPLC .
• Accuracy/Precision : Intraday/interday CV <5% for plasma samples.
• pKa Determination : Use potentiometric titration (this compound pKa1=3.63, pKa2=4.84 at 25°C) to predict tissue distribution .

Q. What are the limitations of AI models in predicting this compound’s structural analogs?

Advanced Research Question
highlights GPT-4o’s errors in identifying analogs (e.g., valsartan vs. gold-standard candesartan). Mitigation strategies:

• Enhanced Prompting : Exclude variants (e.g., “this compound sodium”).
• 3D Similarity Searches : Use PubChem’s Shape Simulator for backbone alignment (e.g., tetrazole ring alignment) .