867160-71-2

Basic information

• Product Name: OSI-906
• Synonyms: OSI-906;cis-3-[8-Amino-1-(2-phenyl-7-quinolinyl)imidazo[1,5-a]pyrazin-3-yl]-1-methylcyclobutanol;Linsitinib;OSI-906 Linsitinib;Cyclobutanol, 3-[8-aMino-1-(2-phenyl-7-quinolinyl)iMidazo[1,5-a]pyrazin-3-yl]-1-Methyl-, cis-;OSI 906AA;(1S,3r)-3-((S)-8-aMino-1-(2-phenylquinolin-7-yl)-2,3-dihydroiMidazo[1,5-a]pyrazin-3-yl)-1-Methylcyclobutanol;(1s,3r)-3-[4-aMino-3-(2-phenylquinolin-7-yl)iMidazo[1,5-a]pyrazin-1-yl]-1-Methylcyclobutan-1-ol
• CAS NO: 867160-71-2
• Molecular Formula: C₂₆H₂₃N₅O
• Molecular Weight: 421.51
• EINECS: 1533716-785-6
• Product Categories: Amines;Aromatics;Heterocycles;Intermediates & Fine Chemicals;Pharmaceuticals;Tyrosine Kinase Inhibitors;Inhibitors
• Mol File: 867160-71-2.mol

Chemical Properties

• Appearance: /
• Density: 1.39
• Storage Temp.: -20°C
• Solubility: Soluble in DMSO (up to 30 mg/ml)
• PKA: 14.84±0.40(Predicted)
• Stability: Stable for 1 year from date of purchase as supplied. Solutions in DMSO may be stored at -20°C for up to 2 months.
• CAS DataBase Reference: OSI-906(CAS DataBase Reference)
• NIST Chemistry Reference: OSI-906(867160-71-2)
• EPA Substance Registry System: OSI-906(867160-71-2)

Safety Data

• Hazardous Substances Data: 867160-71-2(Hazardous Substances Data)

Usage

Uses

Used in Oncology:
OSI-906 is used as an anticancer agent for its potential to target the IGF-1R and InsR kinases, which have been implicated in the promotion of tumorigenesis, metastasis, and resistance to cancer therapies. Its dual inhibition of these receptors makes it a promising candidate for the treatment of various solid tumors and hematologic neoplasias.
Used in Drug Development:
OSI-906 is used as a potent IGF-1R inhibitor in the development of novel cancer therapies. Its selectivity and potency make it a valuable compound for research and development in the field of oncology, with the potential to improve treatment outcomes for patients with cancer.
Used in Preclinical Research:
OSI-906 is used as a research tool in preclinical studies to investigate the role of IGF-1R and InsR in cancer progression and to evaluate the efficacy of dual inhibition as a therapeutic strategy. Its use in preclinical models helps to advance our understanding of the molecular mechanisms underlying cancer development and resistance to therapy.
Used in Predictive Pharmacodynamics:
OSI-906 is used in the development of a rapid, non-invasive method to predict the pharmacodynamic response to the compound. This method can help to identify patients who are more likely to respond to treatment with OSI-906, potentially improving treatment outcomes and reducing side effects for those who are less likely to benefit.

In vitro

OSI-906 inhibits IGF-1R autophosphorylation and activation of the downstream signaling proteins Akt, ERK1/2 and S6 kinase with IC50 of 0.028 to 0.13 μM. OSI-906 enables an intermediate conformation of the target protein through interactions with the C-helix. OSI-906 displays favorable metabolic stability in liver microsomes. OSI-906 fully inhibits both IR and IGF-1R phosphorylation at a concentration of 1 μM. OSI-906 inhibits proliferation of several tumor cell lines including non-small-cell lung cancer and colorectal cancer (CRC) tumor cell line with EC50 of 0.021 to 0.810 μM.

In vivo

OSI-906 inhibits tumor growth in an IGF-1R-driven xenograft mouse model, with 100% TGI and 55% regression at a dose of 75 mg/kg and 60% TGI and no regression at a dose of 25 mg/kg. OSI-906 administration induces different elimination half-lives of itself in dog, rat and mice, the elimination half-lives are 1.18 hours, 2.64 hours and 2.14 hours, respectively. OSI-906 administration at different single dose once-daily in femal Sprague-Dawley rat and femal CD-1 mouse reveal that the Vmax is not dose-proportional to OSI-906 dose. OSI-906 elevates the blood glucose levels at a dose of 25 mg/kg after 12 days administration. OSI-906 administration at a single dose of 75 mg/kg in IGF-1R-driven full-length human IGF-1R (LISN) xenograft mouse model achieve maximal inhibition of IGF-1R phosphorylation (80%) between 4 and 24 hours with plasma drug concentrations of 26.6-4.77 μM. OSI-906 administered as a single dose of at 60 mg/kg in NCI-H292 xenografts mice inhibits uptake of glucose at 2, 4, and 24 hours post-treatment in vivo. OSI-906 inhibits the growth of tumors in NCI-H292 xenograft mouse model.

References

1) Mulvihill?et al.?(2009),?Discovery of OSI-906: a selective and orally efficacious inhibitor of the IGF-1 receptor and insulin receptor; Future Med. Chem.?1?1153 2) Bendell?et al.?(2015),?A phase Ib study of linsitinib (OSI-906), a dual inhibitor of IGF-1R and IR tyrosine kinase, in combination with everolimus as treatment for patients with refractory metastatic colorectal cancer; Invest. New Drugs?33?187 3) Pivonello?et al.?(2016),?The dual targeting of insulin and insulin-like growth factor 1 receptor enhances the mTOR inhibitor-mediated antitumor efficacy in hepatocellular carcinoma?; Oncotarget?7?9718 4) Lee?et al.?(2016),?Inhibition of IGF1R signaling abrogates resistance to afatinib (BIBW2992) in EGFR T790M mutant lung cancer cells; Mol. Carcinog.?55?991 5) Macaulay?et al.?(2016),?Phase I Dose-Escalation Study of Linsitinib (OSI-906) and Erlotinib in Patients with Advanced Solid Tumors; Clin. Cancer Res.?22?2897 6) De Lint?et al.?(2016),?Sensitizing Triple-Negative Breast Cancer to PI3K Inhibition by Cotargeting IGF1R; Mol. Cancer Ther.?15?1545

Synthetic route

2-phenyl-7-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-quinoline (867164-54-3) + cis-3-(8-amino-1-bromo-imidazo[1,5-a]pyrazin-3-yl)-1-methylcyclobutanol (936901-75-6) → linsitinib (867160-71-2)

Conditions	Yield
Stage #1: 2-phenyl-7-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-quinoline; cis-3-(8-amino-1-bromo-imidazo[1,5-a]pyrazin-3-yl)-1-methylcyclobutanol With caesium carbonate; triphenylphosphine In water; N,N-dimethyl-formamide at 95 - 105℃; Industry scale; Inert atmosphere; Stage #2: palladium diacetate In N,N-dimethyl-formamide Industry scale; Inert atmosphere;	65%

3-(1-bromo-8-chloroimidazo[1,5-a]pyrazin-3-yl)cyclobutanone (936901-73-4) → linsitinib (867160-71-2)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: tetrahydrofuran / -65 - -45 °C / Industry scale 1.2: 10 °C / Industry scale; Inert atmosphere 2.1: ammonia / isopropyl alcohol; water / 18 h / 75 - 85 °C / Sealed vessel; Industry scale 3.1: caesium carbonate / triphenylphosphine / N,N-dimethyl-formamide; water / 95 - 105 °C / Industry scale; Inert atmosphere 3.2: Industry scale; Inert atmosphere View Scheme

L-Tartaric acid (87-69-4) + linsitinib (867160-71-2) → cis-8-amino-3-(3-hydroxy-3-methyl-cyclobutyl)-1-(2-phenyl-quinolin-7-yl)-imidazo[1,5-a]pyrazin-7-ium 3-carboxy-2,3-dihydroxy-propionate

Conditions	Yield
In ethanol

linsitinib (867160-71-2) + (2E)-but-2-enedioic acid (110-17-8) → cis-8-amino-3-(3-hydroxy-3-methyl-cyclobutyl)-1-(2-phenyl-quinolin-7-yl)-imidazo[1,5-a]pyrazin-7-ium 3-carboxy-acrylate

Conditions	Yield
In ethanol

methanesulfonic acid (75-75-2) + linsitinib (867160-71-2) → cis-8-amino-3-(3-hydroxy-3-methyl-cyclobutyl)-1-(2-phenyl-quinolin-7-yl)-imidazo[1,5-a]pyrazin-7-ium methanesulfonate (1356958-93-4)

Conditions	Yield
In isopropyl alcohol

linsitinib (867160-71-2) → cis-8-amino-3-(3-hydroxy-3-methyl-cyclobutyl)-1-(2-phenyl-quinolin-7-yl)-imidazo[1,5-a]pyrazin-7-ium chloride (1356958-77-4)

Conditions	Yield
With hydrogenchloride In water

linsitinib (867160-71-2) → cis-8-amino-3-(3-hydroxy-3-methyl-cyclobutyl)-1-(2-phenyl-quinolin-7-yl)-imidazo[1,5-a]pyrazin-7-ium hydrogensulfate

Conditions	Yield
With sulfuric acid In ethanol

Upstream product

• 936901-73-4 3-(1-bromo-8-chloroimidazo[1,5-a]pyrazin-3-yl)cyclobutanone 
• 867164-54-3 2-phenyl-7-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-quinoline 
• 936901-75-6 cis-3-(8-amino-1-bromo-imidazo[1,5-a]pyrazin-3-yl)-1-methylcyclobutanol 

Downstream Products

• 1356958-93-4 cis-8-amino-3-(3-hydroxy-3-methyl-cyclobutyl)-1-(2-phenyl-quinolin-7-yl)-imidazo[1,5-a]pyrazin-7-ium methanesulfonate 
• 1356958-77-4 cis-8-amino-3-(3-hydroxy-3-methyl-cyclobutyl)-1-(2-phenyl-quinolin-7-yl)-imidazo[1,5-a]pyrazin-7-ium chloride 

Relevant articles and documents

PROCESS FOR THE PREPARATION OF THE COMPOUND OSI - 906

Process for preparing the tyrosine kinase inhibitor OSI-906 comprises coupling Compound (2) with Compound (6) under specified conditions.