Home GPCR & G Protein Angiotensin Receptor antagonist Losartan Carboxylic Acid (EXP-3174)

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Losartan Carboxylic Acid (EXP-3174) Angiotensin Receptor antagonist

Cat.No.S5980

Losartan Carboxylic Acid (E-3174, EXP-3174), an active carboxylic acid metabolite of Losartan, is a non-peptide angiotensin II (AT1) receptor antagonist. This compound inhibits the specific binding of [125I]-angiotensin II to VSMC with IC50 of 1.1 nM.
Losartan Carboxylic Acid (EXP-3174) Angiotensin Receptor antagonist Chemical Structure

Chemical Structure

Molecular Weight: 436.89

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Quality Control

Batch: S598001 DMSO]87 mg/mL]false]Ethanol]87 mg/mL]false]Water]Insoluble]false Purity: 99.41%
99.41

Solubility

In vitro
Batch:

DMSO : 87 mg/mL (199.13 mM)
(Moisture-contaminated DMSO may reduce solubility. Use fresh, anhydrous DMSO.)

Ethanol : 87 mg/mL

Water : Insoluble

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In vivo
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Chemical Information, Storage & Stability

Molecular Weight 436.89 Formula

C22H21ClN6O2

 Storage (From the date of receipt) 3 years -20°C powder
CAS No. 124750-92-1 -- Storage of Stock Solutions

Synonyms E-3174 Smiles CCCCC1=NC(=C([N]1CC2=CC=C(C=C2)C3=CC=CC=C3C4=N[NH]N=N4)C(O)=O)Cl

Mechanism of Action

Targets/IC50/Ki
binding of [125I]-angiotensin II to VSMC
(Cell-free assay)
1.1 nM
In vitro

Losartan Carboxylic Acid (EXP-3174) competes in vitro with the binding of angiotensin II to AT1 receptors, with an IC50 of 20 nmol/L. It increases AMPK phosphorylation in a time- and dose-dependent manner in VSMCs, as well as ACC phosphorylation—a major downstream target protein in the AMPK signaling cascade—and LKB1 phosphorylation, an upstream kinase of AMPK. This compound also elevates p53 and p21 expression in a time-dependent manner, while p27 levels remain unchanged. It suppresses Ang II-induced Rb phosphorylation, along with cyclin D and cyclin E expression, which are essential for cell cycle progression. The mechanism of growth suppression by losartan involves G0/G1 cell cycle arrest, reversible through AMPK inhibition (e.g., compound C or AMPK siRNA), but not via apoptosis.
In vivo

Losartan has a major active metabolite, EXP 3174. Administered intravenously, this compound is 10 to 20 times more potent than losartan and has a longer duration of action. However, the oral bioavailability of EXP 3174 is very low. Losartan has a bioavailability of about 33%, the half-life averages 2 h (6-9 hours), and the rate of protein binding is 98.7% when dosed at 50-100 mg/d. Treatment with losartan ameliorates the loss in the number and function of endothelial progenitor cells (EPCs) in hypertensive rats.
References
  • [4] https://pubmed.ncbi.nlm.nih.gov/18250561/

Clinical Trial Information

(data from https://clinicaltrials.gov, updated on 2024-05-22)

NCT Number Recruitment Conditions Sponsor/Collaborators Start Date Phases
NCT05407220 Unknown status
Healthy
Hanmi Pharmaceutical Company Limited
 June 8 2022 Phase 1
NCT05191563 Completed
Healthy
Hanmi Pharmaceutical Company Limited
 July 31 2021 Phase 1
NCT04322266 Completed
Healthy
Hanmi Pharmaceutical Company Limited
 December 21 2018 Phase 1
NCT04081844 Completed
Healthy
Hanmi Pharmaceutical Company Limited
 May 3 2018 Phase 1

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