Retinol-binding protein 4 (RBP4)

Retinol-binding protein 4 (RBP4) is a serum protein that transports Vitamin A. RBP4 is correlated with numerous diseases and metabolic syndromes, including insulin resistance in type 2 diabetes, cardiovascular diseases, obesity, and macular degeneration. Recently, RBP4 antagonists and protein synthesis inhibitors are under development to regulate the effect of RBP4. Several RBP4 antagonists, especially BPN-14136, have demonstrated promising safety profiles and potential therapeutic benefits in animal studies. Two RBP4 antagonists, specifically tinlarebant and STG-001 are currently undergoing clinical trials. Some antidiabetic drugs and nutraceuticals have been reported to reduce RBP4 expression, but more clinical data is needed to evaluate their therapeutical benefits. As regulating RBP4 levels or its activities would benefit a wide range of patients, further research is highly recommended to develop clinically useful RBP4 antagonists or protein synthesis inhibitors [1].

Tinlarebant is an orally administered retinal binding protein-4 (RBP4) antagonist. RBP4 is responsible for delivery of retinol from liver to extrahepatic tissues including the eye. The rationale behind using tinlarebant is to reduce the serum RBP-4, which would lead to a subsequent reduction in levels of retinol in the retina, thereby checking the levels of bisretinoids. Tinlarebant has received a fast-track designation from the FDA in May 2022 and received the Sakigake designation, which expedites the approval for innovative treatments targeting serious ailments, in Japan in June 2024. This designation offers prioritized consultation, pre-application support, expedited review, dedicated review partners, and extended re-examination periods for expediting the approval process. The 2-year phase 2 trial for tinlarebant showed that patients receiving the drug showed sustained lower lesion growth as compared to patients enrolled in ProgStar trial having similar baseline characteristics (p = 0.001). The pivotal global phase 3 DRAGON trial has showed that tinlarebant is well-tolerated and has a consistent safety profile with stabilization of visual acuity in the 1-year interim analysis [2].

[1]. Retinol binding protein 4 antagonists and protein synthesis inhibitors: Potential for therapeutic development. Eur J Med Chem. 2021 Dec 15:226:113856.

[2]. Stargardt's Disease: Molecular Pathogenesis and Current Therapeutic Landscape. Int J Mol Sci. 2025 Jul 21;26(14):7006.

TINLAREBANT is a small molecule drug that has completed up to three Phase III clinical trials (covering all indications) and has three investigational indications.

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Given their potential therapeutic benefits and good safety profile, non-retinoic acid RBP4 antagonists may represent a promising class of potential therapeutic agents. Currently, two non-retinoic acid RBP4 antagonists are undergoing clinical trials: tinlarebant (BPN-14967, ACTRN12621000549820) and STG-001 (NCT04489511) for the treatment of STGD. [1]

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The function of RBP4 and its association with human diseases have been extensively studied. It has been reported that many important physiological functions depend on retinol provided by RBP4 or are affected by serum RBP4 levels. Recently, some studies have focused on developing RBP4 antagonists or synthetic inhibitors to reduce the role of RBP4 in certain disease states. Antagonizing RBP4 has great potential in the treatment of a variety of diseases, such as type 2 diabetes mellitus (T2DM), age-related macular degeneration (AMD), or STGD. [1]

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Retinol-binding protein 4 (RBP4) is a serum protein responsible for transporting vitamin A. RBP4 is associated with a variety of diseases and metabolic syndromes, including insulin resistance in type 2 diabetes, cardiovascular disease, obesity, and macular degeneration. In recent years, RBP4 antagonists and protein synthesis inhibitors have been developed to modulate the role of RBP4. Some RBP4 antagonists, particularly BPN-14136, have shown good safety and potential therapeutic benefits in animal studies. Currently, two RBP4 antagonists, tinlarebant (Belite Bio) and STG-001 (Stargazer), are undergoing clinical trials. Some antidiabetic drugs and nutritional supplements have been reported to reduce RBP4 expression, but more clinical data are needed to evaluate their therapeutic benefits. Since regulating RBP4 levels or its activity would benefit many patients, further research is strongly recommended to develop RBP4 antagonists or protein synthesis inhibitors with clinical value. [1] Stargardt disease (STGD1) is an autosomal recessive juvenile macular degeneration caused by mutations in the ABCA4 gene, resulting in impaired clearance of toxic retinoid byproducts in the retinal pigment epithelium (RPE). This leads to lipofuscin buildup, oxidative stress, photoreceptor degeneration, and central vision loss. More than 1,200 pathogenic/probable pathogenic ABCA4 variants highlight the genetic heterogeneity of STGD1, which manifests as progressive central vision loss and is phenotyped by environmental factors such as deep intron variants, modified genes, and light exposure. ABCA4 variants also exhibit varying penetrance and geographic distribution. As there is currently no approved treatment, investigational therapies are being developed to address different aspects of the disease pathology. Small molecule therapies target vitamin A dimerization (e.g., ALK-001), inhibit lipofuscin accumulation (e.g., soralazine), or regulate visual circulation (e.g., emizole hydrochloride). Gene therapy trials are exploring ABCA4 complementation therapies, including strategies such as RNA exon editing (ACDN-01) and bioengineered ambient light-activated opsins. RORA gene therapy (phase II/III) aims to address issues such as oxidative stress, inflammation, lipid metabolism, and complement system dysregulation. Trials such as DRAGON (phase III, tinlarebant) and STARLIGHT (phase II, bioengineered opsin) have shown promise, but optimizing efficacy remains a challenge. Since establishing genotype-phenotype correlations remains a key issue, the future of STGD1 therapy may depend on approaches that target oxidative stress, lipid metabolism, inflammation, complement regulation, and gene repair. [2]

C21H21F5N4O2

456.409062147141

456.158

1821327-95-0

92044505

Typically exists as solid at room temperature

1.4±0.1 g/cm3

651.1±55.0 °C at 760 mmHg

347.6±31.5 °C

0.0±1.9 mmHg at 25°C

1.555

0.73

1

8

2

32

715

0

FC1=C(C=CC(=C1C(F)(F)F)C1CCN(C(C2C3=C(CN(C(C)=O)CC3)NN=2)=O)CC1)F

HAGSLCBZFRRBLS-UHFFFAOYSA-N

InChI=1S/C21H21F5N4O2/c1-11(31)30-9-6-14-16(10-30)27-28-19(14)20(32)29-7-4-12(5-8-29)13-2-3-15(22)18(23)17(13)21(24,25)26/h2-3,12H,4-10H2,1H3,(H,27,28)

1-[3-[4-[3,4-difluoro-2-(trifluoromethyl)phenyl]piperidine-1-carbonyl]-1,4,5,7-tetrahydropyrazolo[3,4-c]pyridin-6-yl]ethanone

Tinlarebant; ACTRN12621000549820; Tinlarebant [USAN]; BPN14967; LBS-008; 63WI9S8P1M; UNII-63WI9S8P1M; TINLAREBANT [INN]; ...; 1821327-95-0; BPN-14967; ACTRN-12621000549820

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)

May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples

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.)