Retinoic acid-related orphan receptor gamma t (RORγt). Bevurogant (BI 730357) is a RORγt antagonist. [1]
Bevurogant targets the retinoic acid receptor-related orphan receptor gamma t (RORγt), a nuclear receptor transcription factor critical for the differentiation of Th17 cells and the production of pro-inflammatory cytokines like IL-17A and IL-22. As an inverse agonist, it binds to RORγt and suppresses its transcriptional activity, thereby inhibiting the Th17-mediated inflammatory pathway. This mechanism is relevant for chronic inflammatory and autoimmune diseases such as psoriasis. The compound serves as a clinical-stage reference for studying RORγt-related safety endpoints and next-generation inhibitor pharmacology.

In vitro, Bevurogant demonstrates potent RORγt inverse agonist activity with an IC₅₀ of 150 nM in reporter gene assays (RGA). It inhibits the secretion of IL-17A from human peripheral blood mononuclear cells (PBMCs) with an IC₅₀ of 24 nM. These biochemical potencies establish it as a moderate-potency compound suitable for partial target-engagement studies. The compound is used as a reference standard for toxicology benchmarking and comparative pharmacology of next-generation RORγt inhibitors.

Assessing drug-drug interactions for new investigational compounds typically requires multiple trials, each evaluating different drugs with distinct transporter specificities. However, employing a cocktail of drugs that target various transporters allows a single study to simultaneously assess the pharmacokinetics of each component, thereby reducing the number of clinical DDI trials needed during drug development. This study aimed to evaluate the impact of steady-state BI 730357 (bevurogant) on the pharmacokinetics of a validated and optimized four-component transporter cocktail. This Phase I trial employed an open-label, non-randomized, two-period, fixed-sequence design. Healthy subjects aged 18 to 55 years with a body mass index between 18.5 and 29.9 kg/m² received a transporter cocktail (0.25 mg digoxin, 1 mg furosemide, 10 mg metformin hydrochloride, and 10 mg rosuvastatin) either alone or together with BI 730357. During the reference period (Period 1), the cocktail was administered 90 minutes after breakfast. Following a washout period, during the test period (Period 2), subjects received BI 730357 twice daily for 13 days, with the transporter cocktail given on day 1. Primary endpoints included the area under the plasma concentration-time curve from time zero extrapolated to infinity (AUC₀-∞) and the maximum observed plasma concentration (Cmax). The secondary endpoint was the AUC from time zero to the last quantifiable time point (AUC₀-tz). At steady state, BI 730357 increased digoxin exposure by 48% to 94%, had minimal impact on metformin (‑2% to ‑9%), and slightly increased furosemide (12% to 18%) and rosuvastatin (19% to 39%) exposure. Consequently, no clinically meaningful inhibition of the transporters OCT2, MATE-1, MATE-2K, OAT1, OAT3, OATP1B1, or OATP1B3 was observed. While the pharmacokinetic parameters of the endogenous biomarkers coproporphyrin I and III (probes for OATP1B1/1B3) remained within bioequivalence limits, the PK parameters of rosuvastatin (AUC₀-∞, Cmax, AUC₀-tz) exceeded these boundaries, suggesting potential inhibition of breast cancer resistance protein. BI 730357 was found to be safe and well tolerated. This trial confirms that the transporter cocktail containing digoxin, furosemide, metformin, and rosuvastatin is a useful and tolerable tool for assessing drug-transporter interactions in vivo. [1]

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In vivo, Bevurogant demonstrated clinical efficacy as a benchmark for preclinical psoriasis models, achieving 30% PASI75 improvement at a 200 mg dose in Phase II trials. However, its clinical development was discontinued due to preclinical carcinogenicity signals. The compound serves as a critical toxicology reference for de-risking safer analogs. Its efficacy profile provides a benchmark for translational research in psoriasis and other Th17-driven autoimmune diseases.

Non-cell-based enzyme/receptor binding assays for Bevurogant typically involve competitive binding studies using purified RORγt protein. Standard protocols include incubating varying concentrations of the test compound with the RORγt ligand-binding domain and a radiolabeled or fluorescent probe in appropriate buffer systems, followed by separation of bound from free ligand via filtration or fluorescence polarization. Binding affinity (IC₅₀ or Kᵢ values) is calculated using nonlinear regression analysis. Surface plasmon resonance (SPR) or isothermal titration calorimetry (ITC) may also be employed to measure direct binding interactions. The compound's moderate potency makes it suitable for partial target-engagement studies.

Cell-based assays for Bevurogant typically utilize reporter gene assays (RGA) with cells expressing RORγt and a luciferase reporter, or human peripheral blood mononuclear cells (PBMCs) stimulated to produce IL-17A. Standard protocols involve culturing cells in appropriate media at 37°C in 5% CO₂, followed by treatment with varying concentrations of the compound (typically 0.01-10 μM) for 18-24 hours. For PBMC assays, IL-17A secretion is measured by ELISA. Reporter gene activity is quantified by luminescence. IC₅₀ values are calculated from dose-response curves. The compound is used as a reference standard in these assays.

In vivo animal studies for Bevurogant typically involve efficacy models of psoriasis and other Th17-driven autoimmune diseases. Standard protocols include oral administration in rodent models (mice or rats) at doses ranging from 10-200 mg/kg, with observations over 7-14 days depending on the study objectives. In IMQ-induced psoriasis mouse models, efficacy is assessed by measuring skin inflammation scores, epidermal thickness, and IL-17A levels. Pharmacodynamic assessments may include blood sampling for compound exposure analysis and cytokine profiling. The compound's clinical efficacy (30% PASI75 at 200 mg) serves as a benchmark for preclinical models. All animal studies must comply with institutional ethical guidelines.

Bevurogant (BI 730357) is primarily metabolized by CYP3A4 in vivo. Coadministration with itraconazole (a strong CYP3A4 inhibitor) increased BI 730357 exposure by approximately 9-fold. [1]
In this study, Bevurogant was administered orally at 300 mg twice daily for 13 days under fed conditions (30 minutes after a standardized breakfast and dinner). This regimen was designed to achieve an exposure of 44,079 ng/mL•h (AUCτ,ss) and a Cmax,ss of 2,201 ng/mL based on population PK modeling, ensuring that the predicted Cmax,ss for drug interaction (959 ng/mL) was reached and accounting for a positive food effect observed previously. [1]
Steady state of Bevurogant was reached within 7 days of dosing. On Day 7 (one day prior to transporter cocktail administration in period 2), the geometric mean Cpre,ss was 1,135 ng/mL (range 597-2,628), AUCτ,ss was 15,724 ng/mL•h (range 8,688-27,396), and Cmax,ss was 1,690 ng/mL (range 954-2,788). [1]

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Pharmacokinetic properties for Bevurogant are consistent with an orally bioavailable small molecule. The compound has a molecular weight of 532.6 g/mol and was developed for oral administration. It reached Phase II clinical trials, indicating acceptable PK properties in humans. The compound's preclinical carcinogenicity finding is a critical toxicology reference. For in vivo administration, formulations using suitable co-solvent systems may be employed. The compound should be stored as powder at -20°C for long-term preservation. Definitive PK parameters such as half-life, Cmax, and AUC are available from clinical studies but not detailed in public sources.

Bevurogant (BI 730357) at steady-state administration of 300 mg twice daily for 13 days was safe and well tolerated in healthy subjects. [1]
Adverse events (AEs) reported were either mild or moderate in severity and resolved without treatment. No serious AEs, AEs of special interest, or trial discontinuations due to AEs were reported. [1]
For Bevurogant alone, 2 subjects reported drug-related AEs: food aversion (n=1, 6.7%) and pain in extremity (n=1, 6.7%). For BI 730357 plus transporter cocktail, 2 subjects reported drug-related AEs: headache (n=2, 13.3%), parosmia (n=1, 6.7%), and malaise (n=1, 6.7%). [1]

[1]. Choi H, et al. The Effect of BI 730357 (Retinoic Acid-Related Orphan Receptor Gamma t Antagonist, Bevurogant) on the Pharmacokinetics of a Transporter Probe Cocktail, Including Digoxin, Furosemide, Metformin, and Rosuvastatin: An Open-Label, Non-randomized, 2-Period Fixed-Sequence Trial in Healthy Subjects. Clin Pharmacol Drug Dev. 2024 Feb;13(2):197-207.

[2]. Compounds as modulators of ror gamma. US20150291607A1.

Bevurogant (BI 730357) at steady-state administration of 300 mg twice daily for 13 days was safe and well tolerated in healthy subjects. [1]
Adverse events (AEs) reported were either mild or moderate in severity and resolved without treatment. No serious AEs, AEs of special interest, or trial discontinuations due to AEs were reported. [1]
For Bevurogant alone, 2 subjects reported drug-related AEs: food aversion (n=1, 6.7%) and pain in extremity (n=1, 6.7%). For BI 730357 plus transporter cocktail, 2 subjects reported drug-related AEs: headache (n=2, 13.3%), parosmia (n=1, 6.7%), and malaise (n=1, 6.7%). [1]

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Bevurogant was discontinued in clinical development due to preclinical carcinogenicity signals. It serves as an essential reference standard for toxicology benchmarking and comparative pharmacology of next-generation RORγt inhibitors. The compound reached Phase II clinical trials for moderate-to-severe plaque psoriasis, where it achieved 30% PASI75 improvement at 200 mg. Its development was advanced by Boehringer Ingelheim. The compound is used as a clinical-stage reference with reported Phase II endpoint data for translational research. It is not an approved drug.

C26H28N8O3S

532.6173

532.2

C, 58.63; H, 5.30; N, 21.04; O, 9.01; S, 6.02

1817773-66-2

118440466

White to light yellow solid powder

1.1

1

9

8

38

1030

1

S(C([H])([H])[H])(C1=C([H])N=C(C([H])=C1[H])C([H])([H])N([H])C1C(N(C2C(=C([H])N=C(C3=C(C([H])([H])[H])N=C([H])N=C3C3([H])C([H])([H])C3([H])[H])N=2)N=1)[C@@]([H])(C([H])([H])[H])C1([H])C([H])([H])C1([H])[H])=O)(=O)=O

HVVHIBHBDCYLDI-HNNXBMFYSA-N

InChI=1S/C26H28N8O3S/c1-14-21(22(17-6-7-17)31-13-30-14)23-29-12-20-25(33-23)34(15(2)16-4-5-16)26(35)24(32-20)28-10-18-8-9-19(11-27-18)38(3,36)37/h8-9,11-13,15-17H,4-7,10H2,1-3H3,(H,28,32)/t15-/m0/s1

8-[(1S)-1-cyclopropylethyl]-2-(4-cyclopropyl-6-methylpyrimidin-5-yl)-6-[(5-methylsulfonylpyridin-2-yl)methylamino]pteridin-7-one

Bevurogant; BI 730357； 1817773-66-2; BI-730357； Bevurogant [INN]; BI730357； 1874HVK11I; 7(8H)-Pteridinone, 8-((1S)-1-cyclopropylethyl)-2-(4-cyclopropyl-6-methyl-5-pyrimidinyl)-6-(((5-(methylsulfonyl)-2-pyridinyl)methyl)amino)-

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)

DMSO: 250 mg/mL (469.4 mM)

Solubility in Formulation 1: ≥ 2.08 mg/mL (3.91 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.08 mg/mL (3.91 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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