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BPO-27, a benzopyrimido-pyrrolo-oxazine-dione analog, is a novel, potent CFTR inhibitor with IC50 of 4 nM. It can be potentially used as a therapeutic for secretory diarrheas and ADPKD because of its druglike properties and low-nanomolar potency for inhibition of CFTR chloride conductance.
| ln Vitro |
In HEK-293T cells, (R)-BPO-27 has a dose-responsive inhibitory action that reduces CFTR current by 50% at 0.53 nM. (R)-BPO-27 has minimal membrane permeability and functions from the cytoplasmic side [1]. (R)-BPO-27 significantly raised the average channel closed time, considerably decreased the average channel open time, and decreased the channel open probability (NPo) from 0.29 to 0.08 in HEK-293T cells expressing human wild-type CFT in a single pass. Patch clamp tests across channels. Yet, none of these parameters are impacted by (S)-BPO-27 [1]. In single-channel electrophysiological tests, (R)-BPO-27 has an IC50 of 600 pM and stabilizes the CFTR channel closed state when injected directly to the cell plasma membrane surface [2]. Following CFTR stimulation, Cl-currents in CFTR-expressing FRT cells were reduced by (R)-BPO-27 (10 μM, 10 min pretreatment), with apparent IC50 values of CPT-cAMP and 8-Br-cGMP, respectively. 5 and 10 nM using an agonist of cAMP. Forskolin-stimulated CFTR Cl-current in FRT cells can be inhibited at an IC50 of 4 nM [3].
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| ln Vivo |
In PK investigations, (R)-BPO-27 (ip; 10 mg/kg) provided sustained therapeutic concentrations in the kidneys and decayed within t1/2≈1.6 hours [1]. (R)-BPO-27 (intraperitoneal injection; 5 mg/kg; 30 minutes before to abdominal surgery) results in intestinal loop weight/length ratios that are comparable to PBS-injected loops by preventing fluid accumulation in closed jejunal loops caused by cholera toxin. The IC50 value for this dose-dependent action is 0.1 mg/kg[3]. (R)-BPO-27 (ip or orally; 5 mg/kg) provides sustained blood (R)-BPO-27 levels for at least 4 hours and demonstrates a sluggish metabolism of (R)-BPO-27. AUC analysis revealed that the oral bioavailability of (R)-BPO-27 was almost 94% in mice pharmacokinetic and toxicology investigations [3].
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| Animal Protocol |
Animal/Disease Models: Female CD1 mice (8-10 weeks old) [3]
Doses: 0.05, 0.15, 0.5, 1.5 and 5 mg/kg Route of Administration: intraperitoneal (ip) injection; 5 mg/kg; 30 minutes before abdominal surgery Experimental Results: Demonstrated significant efficacy in mouse models of cholera and traveler's diarrhea. |
| References |
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| Molecular Formula |
C26H18BRN3O6
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|---|---|
| Molecular Weight |
548.3416
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| Exact Mass |
547.037
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| CAS # |
1415390-47-4
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| Related CAS # |
BPO-27 racemate;1314873-02-3
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| PubChem CID |
71108905
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| Appearance |
White to off-white solid powder
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| LogP |
3.8
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
6
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| Rotatable Bond Count |
3
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| Heavy Atom Count |
36
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| Complexity |
914
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| Defined Atom Stereocenter Count |
1
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| SMILES |
BrC1=C([H])C([H])=C([C@@]2([H])C3=C4C(C(N(C([H])([H])[H])C(N4C([H])([H])[H])=O)=O)=C(C4C([H])=C([H])C([H])=C([H])C=4[H])N3C3C([H])=C(C(=O)O[H])C([H])=C([H])C=3O2)O1
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| InChi Key |
GNHIGSRGYXEQEP-QHCPKHFHSA-N
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| InChi Code |
InChI=1S/C26H18BrN3O6/c1-28-21-19(24(31)29(2)26(28)34)20(13-6-4-3-5-7-13)30-15-12-14(25(32)33)8-9-16(15)36-23(22(21)30)17-10-11-18(27)35-17/h3-12,23H,1-2H3,(H,32,33)/t23-/m0/s1
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| Chemical Name |
(6R)-6-(5-Bromo-2-furanyl)-7,8,9,10-tetrahydro-7,9-dimethyl-8,10-dioxo-11-phenyl-6H-pyrimido[4',5'
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| Synonyms |
BPO 27 BPO27 BPO-27
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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 : ≥ 14.28 mg/mL (~26.04 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 | 1.8237 mL | 9.1184 mL | 18.2369 mL | |
| 5 mM | 0.3647 mL | 1.8237 mL | 3.6474 mL | |
| 10 mM | 0.1824 mL | 0.9118 mL | 1.8237 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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