Angiotensin II type 1 (AT₁) receptor - competitive antagonist. IC50 (for [125I]-AII binding to bovine adrenal cortical membranes) = 8.0 ± 0.8 nM. [2]
No significant binding to AT₂ receptor (IC50 > 100,000 nM). [2]

In vitro activity: Olmesartan Medoxomil significantly reduces liver hydroxyproline content, the mRNA expression of collagen alpha1(I) and alpha-smooth muscle actin (alpha-SMA), and plasma levels of transforming growth factor-beta1 (TGF-beta1). Olmesartan Medoxomil is a pro-drug containing an ester moiety that, after oral administration, is rapidly cleaved to release the active form Olmesartan (RNH-6270). Olmesartan is a highly potent, competitive and selective All AT1 receptor antagonist with almost no antagonistic activity on AT2 and AT4 receptors. Kinase Assay: Olmesartan medoxomil is a potent and selective angiotensin AT1 receptor inhibitor with IC50 of 66.2 μM.

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- Olmesartan medoxomil (prodrug) is rapidly metabolized to its active form, olmesartan (RNH-6270), which was used for in vitro experiments. [1]
- In rat primary hepatic stellate cells (HSCs), angiotensin II (Ang II, 10 nM to 10 μM) induced proliferation (measured by [³H]thymidine incorporation) and collagen synthesis (measured by [³H]proline incorporation). The active metabolite RNH-6270 (10 μM) completely blocked Ang II-induced proliferation (P < 0.01) and reduced Ang II-induced collagen synthesis by 85% (P < 0.001). [1]
- In rat primary HSCs, Ang II (1 nM to 10 μM) dose-dependently increased TGF-β1 production in culture supernatants (P < 0.001 at >1 nM). PDGF-BB also induced TGF-β1 production. Ang II enhanced PDGF-induced TGF-β1 production. RNH-6270 (10 μM) almost completely blocked Ang II-induced TGF-β1 production (P < 0.001). [1]
- In rat primary HSCs, Ang II (10 μM) increased CTGF mRNA expression 1.9-fold (P < 0.001), and RNH-6270 (10 μM) completely blocked this induction (P < 0.01). [1]
- In isolated guinea-pig aortae, olmesartan (active form) caused a marked reduction of the maximal response with little rightward shift of the concentration-response curve for AII-induced contractions (pD₂ value = 9.91 ± 0.07). It was 160, 3.4, 1.2 and 12 times more potent than losartan, EXP3174, CV11974 and saralasin, respectively, in inhibiting AII-induced contractions. Olmesartan had no effect on contractile responses to phenylephrine or potassium chloride. [2]
- In isolated guinea-pig tracheae, bradykinin-induced contractions were significantly potentiated by the ACE inhibitor enalaprilat (10⁻⁷ mol/L), but not by high concentrations of olmesartan (10⁻⁶ to 10⁻⁵ mol/L), indicating that olmesartan does not exhibit ACE inhibitor-like properties (potentiation of bradykinin). [2]

Olmesartan produces a rapid and long-lasting inhibition of All-induced pressor responses in conscious rats. Oralolmesartan medoxomil also inhibits All-pressor response but onset of the action is slower compared with intravenous administration. Olmesartan Medoxomil exhibits dose-dependent antihypertensive effects in several rat and dog models, with the most marked effects seen in high plasma renin models, when compared with normal or low renin types. Olmesartan medoxomil exhibits, beside antihypertensive effects, beneficial effects in animal models of various types of nephrosis and heart failure, and anti-atherogenic effects in hyperlipidaemic animals. Olmesartan Medoxomil dose-dependently ameliorates the colonic histopathological and biochemical injuries in rats, an effect that is comparable or even better than that of the standard Sulfasalazine. Olmesartan medoxomil significantly reduces the induction of hypoxic cor pulmonale not only on echocardiographical observations but also in brain natriuretic peptide (BNP) in chronic hypoxic rats, TGF-beta and endothelin gene expressions in molecular studies.

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- Liver fibrosis model (bile duct-ligated rats): Oral administration of olmesartan medoxomil (1 mg/kg per day, six times a week from Day 7 to Day 20) significantly reduced liver hydroxyproline content (per gram liver: 45% reduction, P < 0.05; total content: 54% reduction, P < 0.01), plasma TGF-β1 levels (79% reduction, P < 0.05), and mRNA expression of collagen α1(I) (44% reduction, P < 0.05) and α-SMA (52% reduction, P < 0.05) compared to bile duct-ligated control rats. Histological analysis showed reduced bile duct proliferation, collagen deposition, and α-SMA-positive cells. [1]
- Antihypertensive effects in spontaneously hypertensive rats (SHR): Oral administration of olmesartan medoxomil (0.01 to 0.3 mg/kg) dose-dependently reduced blood pressure with a long duration of action (24-hour AUC analysis showed it was equipotent to candesartan cilexetil and 30 times more potent than losartan). A single dose of 0.1 mg/kg produced a hypotensive effect with a faster onset of action than candesartan cilexetil (0.1 mg/kg) and losartan (3 mg/kg). [2]
- Renal hypertensive rats (2K1C): Oral olmesartan medoxomil (0.01 to 0.3 mg/kg) dose-dependently reduced blood pressure. The maximal hypotensive response at 0.3 mg/kg was observed 3 hours after administration. [2]
- Renal hypertensive dogs: Oral olmesartan medoxomil (3 and 10 mg/kg for 14 days) caused significant reductions in blood pressure without affecting heart rate. The antihypertensive effect became greater after 7 days of consecutive dosing. The agent caused measurable increases in plasma renin activity and circulating AI and AII concentrations. [2]
- Haemodynamic effects in SHR: A single dose of olmesartan (0.01 or 0.1 mg/kg) lowered blood pressure dose-dependently without affecting heart rate. The higher dose increased cardiac output and decreased total peripheral resistance. Blood flow in the kidneys was markedly increased in a dose-dependent manner. [2]
- Atherosclerosis models: In Watanabe heritable hyperlipidemic rabbits, combination of olmesartan medoxomil (1 mg/kg) with pravastatin (50 mg/kg) for 32 weeks significantly reduced atherosclerotic lesion area and intimal thickness compared to vehicle. In monkeys fed a high-cholesterol diet, olmesartan medoxomil (1 and 10 mg/kg) reduced atherosclerosis in a dose-related manner (65% reduction in the high-dose group). [2]

- AT₁ receptor binding assay: Bovine adrenal cortical membranes (20 μg protein/well) were incubated with 0.1-0.15 nM [125I]-angiotensin II and various concentrations of olmesartan or other antagonists for 2 hours at room temperature. Specific binding was determined as the difference between binding in the absence and presence of 200 μmol/L unlabelled angiotensin II. IC50 values were calculated. [2]
- AT₄ receptor binding assay: Bovine adrenal cortical membranes were incubated with 0.1-0.15 nM [125I]-angiotensin IV for 2 hours at room temperature. Specific binding was determined as the difference between binding in the absence and presence of 200 μmol/L unlabelled angiotensin IV. [2]
- Isolated guinea-pig aorta contraction assay: Male Hartley guinea pigs were sacrificed, and the thoracic aortae were removed and cut into 3-mm rings. The rings were mounted in organ baths containing Krebs-Henseleit solution at 37°C, aerated with 95% O₂/5% CO₂, under a resting tension of 1 g. After 60 min equilibration, cumulative concentration-response curves for angiotensin II (0.3 nM to 3 μM) were obtained. Antagonists were added 20 min before re-determining the concentration-response curves. pA₂ and pD₂ values were calculated. [2]
- Isolated guinea-pig trachea contraction assay: Guinea-pig tracheal strips were mounted in organ baths. Contractions were induced by bradykinin (3 μM) in the presence of enalaprilat (10⁻⁷ M) or olmesartan (10⁻⁶ to 10⁻⁵ M). [2]

- HSC proliferation assay (³H-thymidine incorporation): Rat primary HSCs were cultured in serum-free DMEM with Ang II (0.1 nM to 10 μM) ± RNH-6270 (10 μM) for 48 hours, pulsed with 0.5 μCi/mL [methyl-³H]thymidine for the final 48 hours. Cells were harvested, and incorporated radioactivity was counted by liquid scintillation counter. [1]
- Collagen synthesis assay (³H-proline incorporation): Rat primary HSCs were cultured in serum-free DMEM with Ang II (0.1 nM to 10 μM) ± RNH-6270 (10 μM), containing 0.5 mM 3-aminopropionitrile and 0.1 mM L-ascorbic acid, for 48 hours, pulsed with 0.5 μCi/mL L-[2,3,4,5-³H]proline. Cells were precipitated with TCA, washed, and digested with collagenase. Radioactivity in the collagenase-digestible supernatant was counted. [1]
- TGF-β1 production assay: HSCs were incubated with Ang II (0.1 nM to 10 μM) ± RNH-6270 (10 μM) or PDGF-BB (0.1 to 100 ng/mL) for 48 hours. Culture supernatants were collected, acid-activated to convert latent TGF-β1 to active form, and total TGF-β1 was measured by ELISA. [1]
- CTGF mRNA expression (TaqMan PCR): HSCs were incubated with Ang II (10 μM) ± RNH-6270 (10 μM) for 24 hours. Total RNA was extracted, reverse-transcribed to cDNA, and subjected to TaqMan PCR analysis using specific primers and probes for CTGF and GAPDH (internal control). [1]
- RNA extraction and TaqMan PCR for in vivo samples: Total RNA was isolated from homogenates of whole livers using TRIZOL reagent. cDNA was synthesized using TaqMan Reverse Transcription Reagents. TaqMan PCR was performed using an ABI PRISM 7700 Sequence Detector System with specific primers and probes for collagen α1(I), α-SMA, and GAPDH. [1]

10 to 12-week old male db/db diabetic mice with background strain C57BL/KsJ and their age-matched non-diabetic lean control mice (C57BL) are used.10 non-diabetic control mice and 10 diabetic mice are fed with placebo (0.5% sodium CMC/saline solution), and 10 diabetic mice are fed with 20 mg/kg Olmesartan (MB5704) by daily gavage for 12 weeks. Mice are monitored for blood glucose, body weight and urine output every two weeks. After treatment, mice are euthanized and trunk blood is collected and is centrifuged to obtain plasma which is aliquoted and stored at -80°C. Kidney tissues are removed from mice. For protein extraction slices of the kidney tissue are frozen in liquid nitrogen, and stored at -80°C. Other parts of the kidney tissue are fixed with 4% paraformaldehyde and embedded in paraffin for immunostaining.

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- Bile duct ligation (BDL) liver fibrosis model: Male SD rats (200-250 g) underwent common bile duct ligation. On Day 7, surviving rats were randomly divided into two groups. Olmesartan medoxomil was suspended in 0.5% carboxymethyl cellulose and orally administered at 1 mg/kg, six times a week from Day 7 to Day 20. Control BDL rats received vehicle. Sham-operated rats served as normal controls. On Day 21, animals were euthanized, and liver, spleen, and blood were collected. [1]
- Spontaneously hypertensive rats (SHR): Male SHR (12-16 weeks old) were used. Olmesartan medoxomil (0.01, 0.03, 0.1, 0.3 mg/kg), candesartan cilexetil (0.1 mg/kg), losartan (3 mg/kg), or vehicle was administered orally by gavage. Blood pressure and heart rate were measured continuously for 24 hours after dosing using a telemetry system. For furosemide pretreatment, SHR were given furosemide (20 mg/kg, s.c.) once daily for 7 days before the study. [2]
- Renal hypertensive rats (2K1C): Two-kidney, one-clip hypertensive rats were prepared. Olmesartan medoxomil (0.01, 0.03, 0.1, 0.3 mg/kg), candesartan cilexetil (0.1 mg/kg), losartan (3 mg/kg), or vehicle was administered orally by gavage. Blood pressure and heart rate were measured for 24 hours after dosing. [2]
- Renal hypertensive dogs: Conscious male Goldblatt renal hypertensive dogs were used. Olmesartan medoxomil (1, 3, 10 mg/kg) was administered orally in capsules once daily for 14 days, followed by a 7-day washout period. Blood pressure, heart rate, plasma renin activity, AI, AII, aldosterone, epinephrine, norepinephrine, and serum electrolytes were measured. [2]
- Haemodynamic study in SHR: Male SHR (23-27 weeks old) were anesthetized. A single dose of olmesartan (0.01 or 0.1 mg/kg) or vehicle was administered intravenously. Cardiac output and regional blood flow were measured using [¹⁴¹Ce]- and [⁵¹Cr]-labeled microspheres. [2]
- Atherosclerosis model in rabbits: Male Watanabe heritable hyperlipidemic rabbits (10-12 months old) were used. Olmesartan medoxomil (1 mg/kg) and pravastatin (50 mg/kg) alone or in combination were administered orally once daily for 32 weeks. Aortae were excised to measure atherosclerotic lesion area and intimal thickness. [2]
- Atherosclerosis model in monkeys: Cynomolgus monkeys fed a high-cholesterol diet were used. Olmesartan medoxomil (1 or 10 mg/kg) was administered orally once daily for 13 weeks. Aortae were excised to measure atherosclerotic lesion area. [2]

Olmesartan medoxomil is a prodrug that is rapidly absorbed from the gastrointestinal tract after oral administration and completely hydrolyzed to the pharmacologically active metabolite olmesartan during absorption via esterases. The parent drug, olmesartan medoxomil, is not measurable in plasma or excreta. Peak plasma concentrations of olmesartan occur 1-3 hours after administration, with an elimination half-life of 10-15 hours. The absolute bioavailability of olmesartan from olmesartan medoxomil tablets is approximately 26%-28.6%, and food does not affect its absorption. The drug exhibits linear pharmacokinetics, with peak concentration and area under the curve increasing approximately proportionally with dose over the therapeutic dose range (up to 40-80 mg daily). Olmesartan has a low volume of distribution, consistent with limited extravascular tissue distribution. Approximately 40% of systemically available olmesartan is excreted renally, with the remainder excreted in feces following biliary secretion. Renal clearance (0.5-0.7 L/h) is dose-independent. Olmesartan exhibits little or no binding to blood cells. No drug accumulation was observed in healthy Chinese subjects after 7 days of once-daily 20 mg administration. No clinically significant steady-state pharmacokinetic interactions were observed when olmesartan medoxomil was co-administered with digoxin, warfarin, or antacid.

The toxicological profile of olmesartan medoxomil has been well characterized in both preclinical and clinical studies. In clinical trials involving over 3,825 patients, olmesartan medoxomil was generally well-tolerated, with a withdrawal rate due to adverse events of 2.4%, similar to the placebo group (2.7%). The most common adverse reaction was dizziness, occurring in approximately 3% of patients (1% in the placebo group). Other reported adverse events include asthenia, angioedema, anaphylactic reactions, vomiting, pruritus, urticaria, alopecia, and increased blood creatinine levels.
Serious Adverse Reactions and Warnings:
Fetal Toxicity: Olmesartan medoxomil can cause fetal harm. Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. When pregnancy is detected, discontinue olmesartan medoxomil as soon as possible.
Sprue-like Enteropathy: Severe, chronic diarrhea with substantial weight loss has been reported in patients taking olmesartan months to years after drug initiation. Intestinal biopsies often demonstrate villous atrophy. If no other etiology is identified, alternative antihypertensive therapy should be considered. The mechanism is thought to involve excessive consumption of enzymes (PON1 and carboxymethylenebutenolidase) responsible for gliadin digestion during drug hydrolysis.
Impaired Renal Function: In patients whose renal function depends on RAAS activity (e.g., severe congestive heart failure, bilateral or unilateral renal artery stenosis), treatment with olmesartan may be associated with oliguria, progressive azotemia, and acute renal failure.
Hyperkalemia: Monitor serum potassium levels in patients with renal insufficiency, diabetes mellitus, or those concomitantly using potassium-sparing diuretics or potassium supplements.
Cardiovascular Risk in Diabetic Patients on High Dose: The ROADMAP trial and an epidemiologic study suggested that high-dose olmesartan (40 mg/day) in diabetic patients may be associated with an increased risk of cardiovascular mortality (HR 2.0-4.9), though these data remain inconclusive.
Dose adjustment is required in patients with renal or hepatic impairment: patients with severe renal insufficiency (CrCl <20 mL/min) or moderate hepatic insufficiency (Child-Pugh score 7-9) should not exceed a daily dose of 20 mg. Use in children less than 1 year of age is not recommended.

[1]. Br J Pharmacol.2003 Jul;139(6):1085-94;
[2]. J Hypertens Suppl.2001 Jun;19(1):S3-14.

- Olmesartan medoxomil is a prodrug that is rapidly hydrolyzed to its active form, olmesartan (RNH-6270), after oral administration. [1]
- The drug has a slow onset and offset at the AT₁ receptor site compared to losartan. The inhibitory effects of olmesartan persisted more than 90 minutes after removal of the drug by repeated washing, whereas washing readily reversed those of losartan. [2]
- Unlike ACE inhibitors, olmesartan does not potentiate bradykinin-induced contractions, suggesting it should be clinically free of the dry cough syndrome characteristic of ACE inhibitors. [2]
- The antihypertensive efficacy of olmesartan medoxomil is most marked in high plasma renin models (renal hypertensive rats > SHR > normotensive rats > DOCA salt rats). [2]
- Cytochrome P-450 inhibition did not affect the inhibition of AII pressor responses following olmesartan medoxomil, suggesting it may have less inter-patient variability in antihypertensive efficacy compared to losartan. [2]

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Olmesartan medoxomil belongs to the biphenyl class of compounds. Olmesartan medoxomil is a synthetic imidazole derivative prodrug with antihypertensive effects. Upon hydrolysis, olmesartan medoxomil is converted to olmesartan. Olmesartan selectively binds to angiotensin II type 1 (AT1) receptors in vascular smooth muscle and the adrenal glands, thereby competitively inhibiting the binding of angiotensin II to its receptors. This prevents angiotensin II-induced vasoconstriction and reduces aldosterone production, thus preventing aldosterone-stimulated sodium retention and potassium excretion. Olmesartan medoxomil is an angiotensin II type 1 receptor blocker used to treat hypertension. See also: Olmesartan (contains the active ingredient); hydrochlorothiazide; olmesartan medoxomil (one of the ingredients); amlodipine besylate; olmesartan medoxomil (an ingredient)... See more...

C29H30N6O6

558.59

558.222

C, 62.36; H, 5.41; N, 15.05; O, 17.18

144689-63-4

Olmesartan medoxomil;144689-63-4; 144689-24-7; 1347262-29-6 (methyl ester )

130881

White to yellow solid powder

1.4±0.1 g/cm3

804.2±75.0 °C at 760 mmHg

180°C

440.2±37.1 °C

0.0±3.0 mmHg at 25°C

1.661

5.23

2

10

11

41

969

0

CCCC1=NC(=C(N1CC2=CC=C(C=C2)C3=CC=CC=C3C4=NNN=N4)C(=O)OCC5=C(OC(=O)O5)C)C(C)(C)O

UQGKUQLKSCSZGY-UHFFFAOYSA-N

InChI=1S/C29H30N6O6/c1-5-8-23-30-25(29(3,4)38)24(27(36)39-16-22-17(2)40-28(37)41-22)35(23)15-18-11-13-19(14-12-18)20-9-6-7-10-21(20)26-31-33-34-32-26/h6-7,9-14,38H,5,8,15-16H2,1-4H3,(H,31,32,33,34)

1H-Imidazole-5-carboxylic acid, 4-(1-hydroxy-1-methylethyl)-2-propyl-1-((2-(1H-tetrazol-5-yl)(1,1-biphenyl)-4-yl)methyl)-, (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl ester

144689-63-4; Olsertain; CS866; Olmesartan medoxomil; CS 866; CS-866; Olmetec; Azor; Benicar;

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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 (Please use freshly prepared in vivo formulations for optimal results.)