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Baxdrostat is a selective aldosterone synthase (CYP11B2) inhibitor.
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| ln Vitro |
In cellular enzyme assays using G-402 cells transfected with human CYP11B2, Baxdrostat demonstrated potent inhibitory activity with an EC50 of 14 nM. The compound competitively inhibits aldosterone synthase, blocking the conversion of 11-deoxycorticosterone to aldosterone. In vitro studies confirmed that Baxdrostat exhibits a high selectivity ratio for aldosterone synthase compared to 11β-hydroxylase (CYP11B1), with a selectivity factor of approximately 100-fold. The primary metabolite of Baxdrostat, CIN-107-M, also exhibits selectivity for aldosterone synthase over 11β-hydroxylase, with its two enantiomers showing >20-fold greater selectivity for aldosterone synthase.
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| ln Vivo |
In a Phase 2 trial (BrigHTN) involving patients with treatment-resistant hypertension, Baxdrostat (2 mg once daily) significantly reduced blood pressure. The mean seated systolic blood pressure (SBP) reduction from baseline was 15.7 mmHg, with a placebo-adjusted reduction of 9.8 mmHg at 12 weeks. The 1 mg dose achieved a placebo-adjusted SBP reduction of 8.7 mmHg. In a Phase 3 trial (BaxHTN), these results were confirmed, with approximately 40% of patients achieving healthy blood pressure levels (<130 mmHg) compared to fewer than 20% on placebo. In non-human primate studies, Baxdrostat blunted aldosterone production while having no effect on cortisol levels. The drug also demonstrated dose-dependent reductions in plasma aldosterone and mild decreases in plasma sodium levels with increases in potassium levels.
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| Enzyme Assay |
The inhibitory activity of Baxdrostat on human CYP11B2 and CYP11B1 was assessed using a cellular enzyme assay. G-402 cells were transfected with expression plasmids containing the open reading frame (ORF) for either human CYP11B1 or CYP11B2 under the control of a CMV promoter, along with a neomycin resistance marker. Transfected cells were selected and maintained in McCoy's 5a Medium Modified containing 10% fetal calf serum and 400 μg/ml G418 (Geneticin) at 37°C under 5% CO2/95% air. For the assay, cells were plated in 96-well plates and incubated for 16 hours in DMEM/F12 medium containing 2.5% charcoal-treated fetal calf serum and appropriate substrate concentrations (0.3-10 μM 11-deoxycorticosterone for CYP11B2 or 11-deoxycortisol for CYP11B1). After incubation, supernatant aliquots were transferred and analyzed for product concentration (aldosterone for CYP11B2; cortisol for CYP11B1) using homogeneous time-resolved fluorescence (HTRF) assays.
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| Cell Assay |
The cellular activity of Baxdrostat was evaluated using G-402 cells stably expressing human CYP11B2. These cells were maintained in McCoy's 5a Medium Modified containing 10% fetal calf serum and 400 μg/ml G418 at 37°C under an atmosphere of 5% CO2/95% air. For the cellular enzyme assay, cells were plated onto 96-well plates and incubated for 16 hours in DMEM/F12 medium containing 2.5% charcoal-treated fetal calf serum and 0.3-10 μM of the substrate 11-deoxycorticosterone. Following incubation, an aliquot of the supernatant was transferred, and the concentration of the expected product, aldosterone, was determined using HTRF assays.
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| ADME/Pharmacokinetics |
A phase I study in healthy volunteers showed that basilatin had linear pharmacokinetic characteristics in the 0.5–10 mg dose range, with a median time to peak (Tmax) of 2–4 hours and a mean half-life of approximately 15–20 hours [1]. A crossover study showed no significant pharmacokinetic interaction between basilatin and metformin [3].
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| Toxicity/Toxicokinetics |
Baxdrostat was well tolerated in healthy volunteers and patients with refractory hypertension, with no serious adverse events reported. Mild hyperkalemia was observed in some patients. [1][2][br>]
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| References |
[1]. Results from a phase 1, randomized, double-blind, multiple ascending dose study characterizing the pharmacokinetics and demonstrating the safety and selectivity of the aldosterone synthase inhibitor baxdrostat in healthy volunteers. Hypertens Res. 2023 Jan;46(1):108-118.
[2]. The selective aldosterone synthase inhibitor Baxdrostat significantly lowers blood pressure in patients with resistant hypertension. Front Endocrinol (Lausanne). 2022 Dec 9;13:1097968. [3]. Results From a Randomized, Open-Label, Crossover Study Evaluating the Effect of the Aldosterone Synthase Inhibitor Baxdrostat on the Pharmacokinetics of Metformin in Healthy Human Subjects. Am J Cardiovasc Drugs. 2023 May;23(3):277-286. |
| Additional Infomation |
Baxdrostat is an investigational drug for the treatment of refractory hypertension. Its mechanism of action is through targeting excessive aldosterone production. Its selectivity for CYP11B2 avoids the risk of cortisol deficiency [1][2].
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| Molecular Formula |
C22H25N3O2
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|---|---|
| Molecular Weight |
363.452805280685
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| Exact Mass |
363.194
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| Elemental Analysis |
C, 72.70; H, 6.93; N, 11.56; O, 8.80
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| CAS # |
1428652-15-6
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| Related CAS # |
Baxdrostat;1428652-17-8;(S)-Baxdrostat;1428652-16-7
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| PubChem CID |
71535961
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| Appearance |
Off-white to light yellow solid powder
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| LogP |
2.2
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
3
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| Rotatable Bond Count |
3
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| Heavy Atom Count |
27
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| Complexity |
566
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| Defined Atom Stereocenter Count |
0
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| SMILES |
O=C(CC)NC1C2C=NC=C(C3=CC=C4C(CCC(N4C)=O)=C3)C=2CCC1
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| InChi Key |
VDEUDSRUMNAXJG-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C22H25N3O2/c1-3-21(26)24-19-6-4-5-16-17(12-23-13-18(16)19)14-7-9-20-15(11-14)8-10-22(27)25(20)2/h7,9,11-13,19H,3-6,8,10H2,1-2H3,(H,24,26)
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| Chemical Name |
N-[4-(1-methyl-2-oxo-3,4-dihydroquinolin-6-yl)-5,6,7,8-tetrahydroisoquinolin-8-yl]propanamide
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
DMSO: 125 mg/mL (343.93 mM)
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| Solubility (In Vivo) |
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.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *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). View More
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)] Oral Formulations
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). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.7514 mL | 13.7571 mL | 27.5141 mL | |
| 5 mM | 0.5503 mL | 2.7514 mL | 5.5028 mL | |
| 10 mM | 0.2751 mL | 1.3757 mL | 2.7514 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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