| Size | Price | Stock | Qty |
|---|---|---|---|
| 5mg |
|
||
| 10mg |
|
||
| 25mg |
|
||
| 50mg |
|
||
| 100mg |
|
||
| Other Sizes |
Cedirogant (also known as ABBV-157) is a novel and orally active RORγt inverse agonist. Cedirogant can be used for psoriasis research.
| Targets |
Retinoic acid receptor-related orphan receptor gamma, thymus (RORγt) [3, 4].
|
|---|---|
| ln Vitro |
As a master regulator of TH17 cell differentiation and IL-17/22 production, the transcription factor retinoic acid-related orphan receptor γt (RORγt) is a promising target for the treatment of inflammatory diseases. Studies on chronic plaque psoriasis may benefit from the use of cedirogan (ABBV-157) [1].
Cedirogant is an inverse agonist of RORγt that blocks RORγt activity and targets the IL-17/IL-23 signaling pathway implicated in psoriasis pathogenesis [3]. Based on in vitro studies, cedirogant is metabolized by cytochrome P450 (CYP) 3A4, uridine diphosphate glucuronosyl transferases (UGT) 1A1, and UGT1A3 [4]. |
| ln Vivo |
Phase II Clinical Trial in Psoriasis Patients: In a 16-week phase II study (NCT05044234), patients with moderate-to-severe psoriasis received once-daily oral cedirogant 75 mg, 150 mg, 375 mg, or placebo. At week 16 (primary endpoint), PASI 75 achievement rates were 29% (75 mg), 8% (150 mg), 42% (375 mg), and 0% (placebo). Mean percentage improvement in PASI from baseline ranged from 39% to 63% in cedirogant groups vs. 12% in placebo. PASI 50, PASI 90, and PASI 100 rates were numerically higher in cedirogant groups vs. placebo [3].
Biomarker Effects: Serum IL-17A levels decreased from baseline to week 16 in patients receiving cedirogant 150 mg or 375 mg; IL-17F serum levels decreased over time in a dose-dependent manner through week 16 in all cedirogant groups. No changes were observed in placebo group [3]. Phase I Clinical Trial in Healthy Japanese and Chinese Participants: In healthy Japanese participants, single oral doses of cedirogant (75, 225, 395 mg) and multiple once-daily doses (375 mg for 14 days) were evaluated. In both Japanese and Chinese participants, ex vivo IL-17A inhibition increased in a dose-dependent manner, with maximal inhibition (approximately 60-80%) achieved with 375 mg once-daily doses [4]. |
| Cell Assay |
Ex Vivo Whole Blood IL-17A Stimulation Assay: Human whole blood culture supernatants were used to determine IL-17A concentrations using a validated immunoassay. The percentage of inhibition from baseline of ex vivo IL-17A production was calculated for each postdose sample. Baseline was defined as the predose (0 hour) blood sample. The upper limit of quantitation for the assay samples was 8000 pg/mL, and the lower limit of quantitation was 4 pg/mL [4].
|
| Animal Protocol |
Preclinical Toxicology Study in Dogs: A 39-week toxicology study of cedirogant in dogs was conducted. In this study, cedirogant was associated with a rapid decline in the clinical condition of some dogs, characterized mainly by body weight loss and gastrointestinal signs. These preclinical findings led to the voluntary early termination of the phase II clinical study [3].
|
| ADME/Pharmacokinetics |
Single Dose in Japanese Participants: Following single oral doses of cedirogant (75, 225, 395 mg) in healthy Japanese participants, Cmax values were 2.94, 7.75, and 11.9 μg/mL, respectively. Median tmax was 4 hours. Harmonic mean t1/2 ranged from 24 to 25 hours. AUCt values were 63.4, 171, and 335 μg·h/mL, respectively. Cedirogant plasma exposure increased approximately dose proportionally across the dose range [4].
Multiple Dose in Japanese and Chinese Participants: Following 375 mg once-daily for 14 days in Japanese and Chinese participants, steady-state Cmax was 15.6 μg/mL and 17.8 μg/mL, respectively; AUCτ was 204 μg·h/mL and 206 μg·h/mL, respectively. Median tmax was 4-5 hours. Harmonic mean t1/2 was approximately 20 hours. Accumulation ratios for Cmax and AUCτ were 1.32 and 1.31 in Japanese participants, and 1.22 and 1.10 in Chinese participants. Steady state was attained by Day 2 in Japanese participants, and near-steady-state exposures were achieved by Day 2 in Chinese participants [4]. Cross-Study Comparison (Asian vs. Western): Following multiple 375 mg once-daily doses, Day 14 Cmax was 45% higher in Japanese participants and 73% higher in Chinese participants compared with Western participants; Day 14 AUCτ was 38% higher in Japanese participants and 48% higher in Chinese participants compared with Western participants [4]. Phase II Study in Psoriasis Patients: Estimated median cedirogant plasma Cₐᵥg levels were 3.29 μg/mL (75 mg), 5.84 μg/mL (150 mg), and 10.80 μg/mL (375 mg). Cedirogant plasma exposure increased in a manner that was less than proportional to increasing doses, suggesting higher apparent drug clearance with higher doses, possibly due to autoinduction of CYP3A4 [3]. |
| Toxicity/Toxicokinetics |
Human Safety (Phase II Psoriasis Study): Cedirogant was generally well tolerated. Treatment-emergent adverse event (TEAE) rates were similar between placebo and the 75 mg and 150 mg cedirogant groups, and higher in the 375 mg group (67% vs. 38-39%). The most frequent TEAEs in cedirogant-treated patients (n=117) were COVID-19 (6.0%), nausea (3.4%), and worsening of psoriasis (3.4%). Gastrointestinal TEAEs were more common in the 375 mg group (26% vs. 1-8% in other groups). All GI events were nonserious, mild or moderate, and resolved. One event of moderate abdominal discomfort led to study drug discontinuation. No serious infections, opportunistic infections, tuberculosis, herpes zoster, lymphopenia, anemia, major adverse cardiovascular events, or malignancies (excluding NMSC) were reported [3].
Human Safety (Phase I in Japanese/Chinese Participants): Cedirogant regimens tested were generally well tolerated. No clinically significant vital signs, ECG, or laboratory measurements were observed. In Part 2, one participant receiving 375 mg cedirogant reported pharyngitis (Grade 1, mild). No new safety issues were identified [4]. Preclinical Toxicology: A 39-week toxicology study of cedirogant in dogs was associated with a rapid decline in clinical condition in some dogs, characterized mainly by body weight loss and gastrointestinal signs. These findings led to the voluntary early termination of the phase II study [3]. |
| References | |
| Additional Infomation |
Cedirogant is under investigation in clinical trial NCT05044234 (A Study to Assess Adverse Events and Disease Activity With Cedirogant (ABBV-157) in Adult Participants With Moderate to Severe Psoriasis).
Cedirogant (ABBV-157) is an inverse agonist of the nuclear receptor RORγt (retinoic acid receptor-related orphan receptor gamma, thymus) that blocks RORγt activity and targets the IL-17/IL-23 signaling pathway implicated in psoriasis pathogenesis [3, 4]. The phase II study (NCT05044234) was terminated early by the sponsor due to preclinical findings in a 39-week toxicology study in dogs, where cedirogant was associated with rapid clinical decline characterized by body weight loss and gastrointestinal signs [3]. Based on the limited clinical findings, targeting RORγt may influence pathways associated with active psoriasis through the IL-17/IL-23 signaling pathway. Cedirogant development has been discontinued [3]. |
| Molecular Formula |
C24H20CL3F3N2O3
|
|---|---|
| Molecular Weight |
547.781414031982
|
| Exact Mass |
546.05
|
| Elemental Analysis |
C, 52.62; H, 3.68; Cl, 19.41; F, 10.40; N, 5.11; O, 8.76
|
| CAS # |
2055496-11-0
|
| PubChem CID |
124123797
|
| Appearance |
White to off-white solid powder
|
| LogP |
6.1
|
| Hydrogen Bond Donor Count |
1
|
| Hydrogen Bond Acceptor Count |
6
|
| Rotatable Bond Count |
5
|
| Heavy Atom Count |
35
|
| Complexity |
781
|
| Defined Atom Stereocenter Count |
0
|
| SMILES |
ClC1C(=C(C=CC=1C(N1CCC(CC(=O)O)CC1)=O)Cl)CN1C=CC2C=C(C(F)(F)F)C=C(C1=2)Cl
|
| InChi Key |
MNEOHCYSHVKLIC-UHFFFAOYSA-N
|
| InChi Code |
InChI=1S/C24H20Cl3F3N2O3/c25-18-2-1-16(23(35)31-6-3-13(4-7-31)9-20(33)34)21(27)17(18)12-32-8-5-14-10-15(24(28,29)30)11-19(26)22(14)32/h1-2,5,8,10-11,13H,3-4,6-7,9,12H2,(H,33,34)
|
| Chemical Name |
2-[1-[2,4-dichloro-3-[[7-chloro-5-(trifluoromethyl)indol-1-yl]methyl]benzoyl]piperidin-4-yl]acetic acid
|
| Synonyms |
Cedirogant; Cedirogant; 2055496-11-0; WHO 11460; WHO-11460; WHO11460; UNII-X6466M4LVP; Cedirogant [INN]; Cedirogant [USAN]; ABBV-157; ABBV157; ABBV 157
|
| HS Tariff Code |
2934.99.9001
|
| 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)
|
| Solubility (In Vitro) |
DMSO : ~250 mg/mL (~456.39 mM)
|
|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (3.80 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. Solubility in Formulation 2: ≥ 2.08 mg/mL (3.80 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. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.8256 mL | 9.1278 mL | 18.2555 mL | |
| 5 mM | 0.3651 mL | 1.8256 mL | 3.6511 mL | |
| 10 mM | 0.1826 mL | 0.9128 mL | 1.8256 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.
Products are for research use only; We do not sell to patients
Copyright 2020 InvivoChem LLC | All Rights Reserved
