198474-05-4

Basic information

• Product Name: 3-(5-fluoro-indol-3-yl)-pyrrolidine-2,5-dione
• Synonyms: 3-(5-fluoro-indol-3-yl)-pyrrolidine-2,5-dione;3-(5-fluoro-1H-indol-3-yl)pyrrolidine-2,5-dione;PF-06840003;2,5-Pyrrolidinedione, 3-(5-fluoro-1H-indol-3-yl)-;3-(5-Fluoro-1H-indol-3-yl)-2,5-pyrrolidinedione;PF-06840003 (racemate);EOS200271
• CAS NO: 198474-05-4
• Molecular Formula: C₁₂H₉FN₂O₂
• Molecular Weight: 232
• Product Categories: API
• Mol File: 198474-05-4.mol

Chemical Properties

• Appearance: /
• Storage Temp.: Inert atmosphere,Room Temperature
• Solubility: Soluble in DMSO (up to at least 25 mg/ml)
• Stability: Stable for 1 year from date of purchase as supplied. Solutions in DMSO may be stored at -20°C for up to 3 months.
• CAS DataBase Reference: 3-(5-fluoro-indol-3-yl)-pyrrolidine-2,5-dione(CAS DataBase Reference)
• NIST Chemistry Reference: 3-(5-fluoro-indol-3-yl)-pyrrolidine-2,5-dione(198474-05-4)
• EPA Substance Registry System: 3-(5-fluoro-indol-3-yl)-pyrrolidine-2,5-dione(198474-05-4)

Safety Data

• Hazardous Substances Data: 198474-05-4(Hazardous Substances Data)

Usage

Uses

Used in Pharmaceutical Industry:
3-(5-fluoro-indol-3-yl)-pyrrolidine-2,5-dione is used as a novel and selective IDO-1 inhibitor for its potential in cancer treatment. It has demonstrated the ability to reduce intratumoral kynurenine levels by over 80%, inhibit tumor growth as monotherapy, and increase the efficacy of anti-PD-L1 therapy.
Used in Oncology:
In the field of oncology, 3-(5-fluoro-indol-3-yl)-pyrrolidine-2,5-dione is used as an anticancer agent. It has shown promising results in combination therapies, such as when combined with GM-CSF-secreting allogenic pancreatic tumor cell vaccine (GVAX), resulting in increased antitumor efficacy in a murine model of pancreatic ductal adenocarcinoma.

References

1) Crosignani?et al.?(2017),?Discovery of a Novel and Selective Indoleamine-2,3-Dioxygenase (IDO-1) Inhibitor 3-(5-Fluoro-1H-indol-3-yl)pyrrolidine-2,5-dione (EROS200271/PF-06840003) and Its Characterization as a Potential Clinical Candidate;?J. Med. Chem.?60?9617 2) Gomes?et al.?(2018),?Characterization of the Selective Indoleamine-2,3-Dioxygenase-1 (IDO1) Catalytic Inhibitor EOS200271/PF-06840003 Supports IDO1 as a Critical Resistance Mechanism to PD-(L)1 Blockade Therapy;?Mol. Cancer Ther.?9?2530 3) Blair?et al.?(2019),?IDO1 inhibition potentiates vaccine-induced immunity against pancreatic adenocarcinoma;?J. Clin. Invest.?129?1742

Upstream product

• 541-59-3 maleiimide 
• 399-52-0 5-fluoro-1H-indole 

Downstream Products

• 374818-58-3 3-(5-fluoro-indol-3-yl)-2,5-dihydro-1H-pyrrole-2,5-dione 

Relevant articles and documents

Bf3-oet2 catalyzed c3-alkylation of indole: Synthesis of indolylsuccinimidesand their cytotoxicity studies

A simple and efficient BF3-OEt2 promoted C3-alkylation of indole has been developed to obtain3-indolylsuccinimidesfrom commercially available indoles and maleimides, with excellent yields under mild reaction conditions. Furthermore,

Dual-functional conjugates improving cancer immunochemotherapy by inhibiting tubulin polymerization and indoleamine-2,3-dioxygenase

A series of novel conjugates comprising tublin and IDO inhibitors were designed, synthesized and evaluated for their antiproliferative activity. Among them, HI5, composed of combretastatin A-4 (CA-4) and (D)-1-methyltryptophan (D-MT) by a linker, exhibited the most potent antitumor activity, in particular with higher IC50 value (0.07 μM) than CA-4 (0.21 μM) against HeLa cancer cell line. Mechanism studies indicated that HI5 can inhibit tubulin polymerization and cell migration, cause G2/M phase arrest, concurrent induce apoptosis via the mitochondrial dependent apoptosis pathway and cause reactive oxidative stress generation in HeLa cells. Furthermore, HI5 can inhibit IDO expression and decrease kynurenine production, leading to stimulating T cells activation and proliferation to enhance antitumor immunity in vitro. Interestingly, HI5 can effectively limit the tumor growth in the HeLa xenograft mice models without causing significant loss of body weight. Consequently, such a conjugation can be a potent and safe immunochemotherapeutic method for improving cancer therapy.

Synthesis and biological evaluation of new multi-target 3-(1H-indol-3-yl)pyrrolidine-2,5-dione derivatives with potential antidepressant effect

A series of novel 3-(1H-indol-3-yl)pyrrolidine-2,5-dione derivatives were synthesised and evaluated for their 5-HT1A/D2/5-HT2A/5-HT6/5-HT7 receptor affinity and serotonin reuptake inhibition. Most of the evaluated compounds displayed high affinities for 5-HT1A receptors (e.g., 4c Ki = 2.3 nM, 4l Ki = 3.2 nM). The antidepressant activity of the selected compounds was screened in vivo using the forced swim test (FST). The results indicate that compound MW005 (agonist of the pre- and postsynaptic 5-HT1A receptor) exhibited promising affinities for the 5-HT1A/SERT/D2/5-HT6/5-HT7 receptors and showed an antidepressant-like activity in the FST model.

Antitumor immunoregulation conjugate, and preparation method and application thereof

The present invention discloses an antitumor immunoregulation conjugate. An IDO or TDO micromolecular inhibitor group is directly or indirectly introduced at the hydroxyl position of CA-4 by using theactive group hydroxyl group in the structure of the CA-

Discovery of a Novel and Selective Indoleamine 2,3-Dioxygenase (IDO-1) Inhibitor 3-(5-Fluoro-1H-indol-3-yl)pyrrolidine-2,5-dione (EOS200271/PF-06840003) and Its Characterization as a Potential Clinical Candidate

Tumors use tryptophan-catabolizing enzymes such as indoleamine 2,3-dioxygenase (IDO-1) to induce an immunosuppressive environment. IDO-1 is induced in response to inflammatory stimuli and promotes immune tolerance through effector T-cell anergy and enhanced Treg function. As such, IDO-1 is a nexus for the induction of a key immunosuppressive mechanism and represents an important immunotherapeutic target in oncology. Starting from HTS hit 5, IDO-1 inhibitor 6 (EOS200271/PF-06840003) has been developed. The structure-activity relationship around 6 is described and rationalized using the X-ray crystal structure of 6 bound to human IDO-1, which shows that 6, differently from most of the IDO-1 inhibitors described so far, does not bind to the heme iron atom and has a novel binding mode. Clinical candidate 6 shows good potency in an IDO-1 human whole blood assay and also shows a very favorable ADME profile leading to favorable predicted human pharmacokinetic properties, including a predicted half-life of 16-19 h.

COMBINATIONS COMPRISING A PYRROLIDINE-2,5-DIONE IDO1 INHIBITOR AND AN ANTI-BODY

Combinations of the 3-(5-fluoro-1H-indol-3-yl)pyrrolididine-2,5-dione compound with selected anti-cancer or anti-viral agents are provided. Also provided are use of these combinations for the treatment and/or prevention of cancer and endometriosis.

POLYMORPH FORMS OF PYRROLIDINE-2,5-DIONE DERIVATIVES, PHARMACEUTICAL COMPOSITIONS AND METHODS FOR USE AS IDO1 INHIBITORS

Two distinct crystalline forms of a 3-(5-fluoro-1H-indol-3-yl)pyrrolidine-2,5-dione are provided. Also provided are the use of these polymorphs as IDO1 inhibitors and/or for the treatment and/or prevention of cancer and endometriosis.

COMBINATIONS COMPRISING A PYRROLIDINE-2,5-DIONE IDO1 INHIBITOR AND AN ANTI-BODY

Combinations of the 3-(5-fluoro-1H-indol-3-yl)pyrrolididine-2,5-dione compound with an anti-PD1 antibody or anti-PD-L1 antibody as selected anti-cancer or anti-viral agents are provided. Also provided are use of these combinations for the treatment and/or prevention of cancerand endometriosis.

PYRROLIDINE-2, 5-DIONE DERIVATIVES, PHARMACEUTICAL COMPOSITIONS AND METHODS FOR USE AS IDO1 INHIBITORS

The present invention relates to compound of Formula I or pharmaceutically acceptable enantiomers, salts, solvates or prodrugs thereof. The invention further relates to the use of the compounds of Formula I as IDO1 inhibitors. The invention also relates to the use of the compounds of Formula I for the treatment and/or prevention of cancer and endometriosis. The invention also relates to a process for manufacturing compounds of Formula I.

USE OF (3-(1-(3-PHENYL-PROPENYL)-PIPERIDIN-4-YL)-2,3-DIHYDRO-INDOL-1-YL)-(PYRIDIN-4-YL)-METHANONE DERIVATIVES AND RELATED COMPOUNDS AS INSECTICIDES

The use of a compound of formula (I): R3 N Y R1(I) wherein Y is a single bond, C=O, C=S or S(O)71 where m is 0, 1 or 2; R1, R2 , R3 , R4, R8 and Ra are specified organ