1420477-60-6

Basic information

• Product Name: ACP196
• Synonyms: ACP196;acalabrutinib;Benzamide, 4-[8-amino-3-[(2S)-1-(1-oxo-2-butyn-1-yl)-2-pyrrolidinyl]imidazo[1,5-a]pyrazin-1-yl]-N-2-pyridinyl-;(S)-4-(8-amino-3-(1-but-2-ynoylpyrrolidin-2-yl)imidazo[1,5-a]pyrazin-1-yl)-N-(pyridin-2-yl)benzamide;Acalabrutinib (ACP-196);ACP196,Acalabrutinib;4-[8-Amino-3-[(2S)-1-(1-oxo-2-butyn-1-yl)-2-pyrrolidinyl]imidazo[1,5-a]pyrazin-1-yl]-N-2-pyridinylbenzamide;EOS-60753
• CAS NO: 1420477-60-6
• Molecular Formula: C26H23N7O2
• Molecular Weight: 465.50652
• EINECS: 1312995-182-4
• Mol File: 1420477-60-6.mol
• Article Data: 18

Chemical Properties

• Appearance: /
• Density: 1.37±0.1 g/cm3(Predicted)
• Storage Temp.: Refrigerator
• Solubility: Soluble in DMSO (up to at least 25 mg/ml)
• PKA: 11.47±0.70(Predicted)
• 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: ACP196(CAS DataBase Reference)
• NIST Chemistry Reference: ACP196(1420477-60-6)
• EPA Substance Registry System: ACP196(1420477-60-6)

Safety Data

• Hazardous Substances Data: 1420477-60-6(Hazardous Substances Data)

Usage

Description

ACP196, also known as Acalabrutinib, is a selective second-generation Bruton's tyrosine kinase (BTK) inhibitor with an IC50 of 3 nM. It effectively prevents the activation of the B-cell antigen receptor (BCR) signaling pathway, offering improved target specificity over its predecessor, ibrutinib. ACP196 demonstrates no activity against EGFR and has shown significant selectivity over other TEC kinase family members, making it a promising pharmaceutical candidate for various applications.

Uses

Used in Oncology:
ACP196 is used as an anti-cancer agent, particularly for the treatment of chronic lymphocytic leukemia (CLL). It targets B-cell signaling by inhibiting BTK, a kinase that transmits signals from the B-cell Receptor (BCR). This inhibition helps in managing B-Cell immunodeficiency caused by genetic BTK mutations and has shown great promise in the treatment of CLL.
Used in Drug Development:
In the pharmaceutical industry, ACP196 is utilized for the development of novel drug delivery systems and therapeutic strategies. Its high target specificity and selectivity over other kinases make it an attractive candidate for the design of targeted therapies, potentially leading to improved treatment outcomes and reduced side effects for patients with various types of cancer.

in vitro

In the in vitro signaling assay on primary human CLL cells, acalabrutinib inhibits tyrosine phosphorylation of downstream targets of ERK, IKB, and AKT. Acalabrutinib demonstrates higher selectivity for BTK with IC50 determinations on nine kinases with a cysteine residue in the same position as BTK. Importantly, unlike ibrutinib, acalabrutinib does not inhibit EGFR, ITK, or TEC. acalabrutinib has no effect on EGFR phosphorylation on tyrosine residues Y1068 and Y1173. Compared with ibrutinib, acalabrutinib has much higher IC50(>1000 nM) or virtually no inhibition on kinase activities of ITK, EGFR, ERBB2, ERBB4, JAK3, BLK, FGR, FYN, HCK, LCK, LYN, SRC, and YES1.

in vivo

Oral administration of ACP-196 in mice results in dose-dependent inhibition of anti-IgM-induced CD86 expression in CD19+ splenocytes with an ED50 of 0.34 mg/kg compared to 0.91 mg/kg for ibrutinib. A similar model is used to compare the duration of Btk inhibition after a single oral dose of 25 mg/kg. ACP-196 inhibits CD86 expression >90% at 3h postdose.

IC 50

3 nm

References

1) Wu et al.?(2016),?Acalabrutinib (ACP-196): a second-generation BTK inhibitor;?J. Hematol. Oncol.?9?21 2) Barf?et al.?(2017),?Acalabrutinib (ACP-196): A covalent Bruton Tyrosine Kinase Inhibitor with a Differentiated Selectivity and In Vivo Potency Profile;?J. Pharmacol. Exp. Ther.?363?240 3) Herman?et al.?(2017),?The Bruton’s tyrosine kinase (BTK) inhibitor acalabrutinib demonstrates potent on-target effects and efficacy in two mouse models of chronic lymphocytic leukemia;?Clin. Cancer Res.?23?2831 4) Weber et al.?(2017),?Bruton’s Tyrosine Kinase: An Emerging Key Player in Innate Immunity; Front. Immunol.?8?1454

Upstream product

• 1418307-17-1 benzyl (S)-2-(((3-chloropyrazin-2-yl)methyl)carbamoyl)pyrrolidine-1-carboxylate 
• 1418307-18-2 (S)-2-(8-chloroimidazo[1,5-a]pyrazin-3-yl)-1-pyrrolidinecarboxylic acid benzyl ester 
• 1420478-87-0 benzyl (2S)-2-(1-bromo-8-chloro-imidazo[1,5-a]pyrazin-3-yl)pyrrolidine-1-carboxylate 
• 1420478-88-1 benzyl (2S)-2-(8-amino-1-bromo-imidazo[1,5-a]pyrazin-3-yl)pyrrolidine-1-carboxylate 
• 590-93-2 2-Butynoic acid 
• 1420478-90-5 4-{8-amino-3-[(2S)-pyrrolidin-2-yl]imidazo[1,5-a]pyrazin-1-yl}-N-(pyridin-2-yl)benzamide 
• 1420478-89-2 (S)-2-((1-(4-(pyridin-2-ylcarbamoyl)phenyl)-8-amino)imidazole[1,5-a]pyrazin-2-yl)pyrrolidine1-yl-carboxylic acid benzyl ester 
• 121246-96-6 3-chloro-2-pyrazinecarboxaldehyde 
• 850568-25-1 4-(pyridin-2-yl-aminocarbonyl)benzeneboronic acid 

Relevant articles and documents

NOVEL PROCESS FOR THE PREPARATION OF ACALABRUTINIB AND ITS INTERMEDIATES

The present invention relates to an improved and industrially viable process for the preparation of Acalabrutinib and its Intermediates. The present invention involves less expensive reagents, solvents and the process conditions can be easily adopted for commercial scale. The present invention relates to process for the preparation Acalabrutinib of formula (1) and process for the preparation of Acalabrutinib key starting material.

PROCESSES FOR THE PREPARATION OF 4-{8-AMINO-3-[(2S)-1-(BUT-2-YNOYL)-PYRROLIDIN-2-YL]IMIDAZO[1,5-A]-PYRAZIN-1-YL}N-(PYRIDIN-2-YL)-BENZAMIDE

The present disclosure relates, in general, to improved processes for the preparation of 4-{8-amino-3-[(2S)-1-(but-2-ynoyl)pyrrolidin-2-yl]imidazo[1,5-a]pyrazin-1-yl}-N-(pyridin-2-yl)-benzamide, particularly large-scale processes for manufacturing 4-{8-amino-3-[(2S)-1-(but-2-ynoyl)pyrrolidin-2-yl]imidazo[1,5-a]pyrazin-1-yl}-N-(pyridin-2-yl)benzamide and intermediates used in such processes.

PROCESS FOR THE PREPARATION OF ACALABRUTINIB AND ITS INTERMEDIATES

The present invention provides an improved and industrially viable process for the preparation of Acalabrutinib and its intermediates in high yield and eliminating the use of time-consuming purification process. The present invention also relates to the purification of (S)-4-(8-Amino-3-(pyrrolidin-2-yl)imidazo[1,5-alpyrazin-1-yl)-N-(pyridin-2-yl) benzamide, a key intermediate for the preparation of Acalabrutinib. Further present invention relates to new polymorphic form of Acalabrutinib.