IMIPRIDONE

CAS No. : 1616632-77-9

Molecular Weight, 386.4964

Related CAS #: 41276-02-2 (TIC10 isomer)   1616632-77-9 (free base)   1638178-82-1 (HCl)   1777785-71-3 (HBr)   2007141-57-1 (2HBr)

TIC 10, 0NC 201, OP 10

Synonym: ONC201; ONC 201; ONC-201; NSC350625; NSC-350625; NSC 350625; TIC10; TIC 10; TIC-10; TRAIL inducing compound 10; imipridone

7-benzyl-4-(2-methylbenzyl)-1,2,6,7,8,9-hexahydroimidazo[1,2-a]pyrido[3,4-e]pyrimidin-5(4H)-one

2,4,6,7,8,9-Hexahydro-4-((2-methylphenyl)methyl)-7-phenylmethyl)imidazo)(1,2-a)pyrido(3,4-e)pyrimidin-5(1H)-one

ONC-201 Dihydrochloride

C24H28Cl2N4O

459.4

UNII-53VG71J90J

53VG71J90J

Q27896336

1638178-82-1

Imidazo(1,2-a)pyrido(3,4-E)pyrimidin-5(1H)-one, 2,4,6,7,8,9-hexahydro-4-((2-methylphenyl)methyl)-7-(phenylmethyl)-, hydrochloride (1:2)

• A TRAIL-dependent antitumor agent.

TIC10 (ONC-201) is a potent, orally active, and stable tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) inducer which acts by inhibiting Akt and ERK, consequently activating Foxo3a and significantly inducing cell surface TRAIL. TIC10 can cross the blood-brain barrier.

ONC-201, also known as TIC10, is a potent, orally active, and stable small molecule that transcriptionally induces TRAIL in a p53-independent manner and crosses the blood-brain barrier. TIC10 induces a sustained up-regulation of TRAIL in tumors and normal cells that may contribute to the demonstrable antitumor activity of TIC10. TIC10 inactivates kinases Akt and extracellular signal-regulated kinase (ERK), leading to the translocation of Foxo3a into the nucleus, where it binds to the TRAIL promoter to up-regulate gene transcription. TIC10 is an efficacious antitumor therapeutic agent that acts on tumor cells and their microenvironment to enhance the concentrations of the endogenous tumor suppressor TRAIL.

Akt/ERK Inhibitor ONC201 is a water soluble, orally bioavailable inhibitor of the serine/threonine protein kinase Akt (protein kinase B) and extracellular signal-regulated kinase (ERK), with potential antineoplastic activity. Upon administration, Akt/ERK inhibitor ONC201 binds to and inhibits the activity of Akt and ERK, which may result in inhibition of the phosphatidylinositol 3-kinase (PI3K)/Akt signal transduction pathway as well as the mitogen-activated protein kinase (MAPK)/ERK-mediated pathway. This may lead to the induction of tumor cell apoptosis mediated by tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL)/TRAIL death receptor type 5 (DR5) signaling in AKT/ERK-overexpressing tumor cells. The PI3K/Akt signaling pathway and MAPK/ERK pathway are upregulated in a variety of tumor cell types and play a key role in tumor cell proliferation, differentiation and survival by inhibiting apoptosis. In addition, ONC201 is able to cross the blood-brain barrier.

SYN

Organic & Biomolecular Chemistry, 19(39), 8497-8501; 2021

Herein, we present a copper-catalyzed tandem reaction of 2-aminoimidazolines and ortho-halo(hetero)aryl carboxylic acids that causes the regioselective formation of angularly fused tricyclic 1,2-dihydroimidazo[1,2-a]quinazolin-5(4H)-one derivatives. The reaction involved in the construction of the core six-membered pyrimidone moiety proceeded via regioselective N-arylation–condensation. The presented protocol been successfully applied to accomplish the total synthesis of TIC10/ONC201, which is an active angular isomer acting as a tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL): a sought after anticancer clinical agent.

Click to access d1ob01561c1.pdf

7-Benzyl-4-(2-methylbenzyl)-1,2,6,7,8,9-hexahydroimidazo[1,2-a]pyrido[3,4-e]pyrimidin-5(4H)-one (6): Pale orange semi-solid, 202 mg (0.521 mmol), 52 % Rf = 0.25 (CH3OH/CHCl3 5:95); IR 1490, 1610, 1644, 2882, 2922 cm-1 ; 1H-NMR (500 MHz, CDCl3) δ = 2.39 (s, 3H), 2.54 (t, J = 5.5 Hz, 2H), 2.72 (t, J = 5.7 Hz, 2H), 3.31 (s, 2H), 3.67 (s, 2H), 3.84-3.91 (m, 4H), 5.04 (s, 2H), 7.02-7.04 (m, 1H), 7.08-7.12 (m, 3H), 7.26- 7.34 (m, 5H). 13C{1H}-NMR (101 MHz, CDCl3) δ = 19.3, 26.8, 43.4, 46.9, 48.2, 49.6, 50.45, 62.3, 102.1, 125.2, 125.9, 126.8, 127.4, 128.45, 129.2, 130.2, 134.2, 135.6, 137.9, 145.7, 153.3, 161.4; MS (ESI, m/z): [M+H]+ 387; HRMS (ESI, m/z): calcd for C24H27N4O [M+H]+ found 387.2183.

PATENT

https://patents.google.com/patent/WO2017132661A2/en

Scheme 1.

Scheme 2.

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CLIP

https://mdanderson.elsevierpure.com/en/publications/discovery-and-clinical-introduction-of-first-in-class-imipridone-Discovery and clinical introduction of first-in-class imipridone ONC201

Abstract

ONC201 is the founding member of a novel class of anti-cancer compounds called imipridones that is currently in Phase II clinical trials in multiple advanced cancers. Since the discovery of ONC201 as a p53-independent inducer of TRAIL gene transcription, preclinical studies have determined that ONC201 has anti-proliferative and pro-apoptotic effects against a broad range of tumor cells but not normal cells. The mechanism of action of ONC201 involves engagement of PERK-independent activation of the integrated stress response, leading to tumor upregulation of DR5 and dual Akt/ERK inactivation, and consequent Foxo3a activation leading to upregulation of the death ligand TRAIL. ONC201 is orally active with infrequent dosing in animals models, causes sustained pharmacodynamic effects, and is not genotoxic. The first-in-human clinical trial of ONC201 in advanced aggressive refractory solid tumors confirmed that ONC201 is exceptionally well-tolerated and established the recommended phase II dose of 625 mg administered orally every three weeks defined by drug exposure comparable to efficacious levels in preclinical models. Clinical trials are evaluating the single agent efficacy of ONC201 in multiple solid tumors and hematological malignancies and exploring alternative dosing regimens. In addition, chemical analogs that have shown promise in other oncology indications are in pre-clinical development. In summary, the imipridone family that comprises ONC201 and its chemical analogs represent a new class of anti-cancer therapy with a unique mechanism of action being translated in ongoing clinical trials.

////////////IMIPRIDONE, TIC 10, ONC 201, NSC 350625, OP 10, Fast Track Designation, Orphan Drug Designation, Rare Pediatric Disease Designation, PHASE 3, GLIOMA, CHIMERIX

O=C1N(CC2=CC=CC=C2C)C3=NCCN3C4=C1CN(CC5=CC=CC=C5)CC4