Synonym
A966492; A 966492; A-966492.
IUPAC/Chemical Name
(S)-2-(2-fluoro-4-(pyrrolidin-2-yl)phenyl)-1H-benzimidazole-4-carboxamide
InChi Key
AHIVQGOUBLVTCB-AWEZNQCLSA-N
InChi Code
InChI=1S/C18H17FN4O/c19-13-9-10(14-5-2-8-21-14)6-7-11(13)18-22-15-4-1-3-12(17(20)24)16(15)23-18/h1,3-4,6-7,9,14,21H,2,5,8H2,(H2,20,24)(H,22,23)/t14-/m0/s1
SMILES Code
O=C(C1=C2N=C(C3=CC=C([C@H]4NCCC4)C=C3F)NC2=CC=C1)N
Appearance
white solid powder
Purity
>98% (or refer to the Certificate of Analysis)
Shipping Condition
Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.
Storage Condition
Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).
Solubility
Soluble in DMSO, not in water
Shelf Life
>2 years if stored properly
Drug Formulation
This drug may be formulated in DMSO
Stock Solution Storage
0 - 4 C for short term (days to weeks), or -20 C for long term (months).
HS Tariff Code
2934.99.9001
Biological target:
A-966492 is a novel and potent inhibitor of PARP1 and PARP2 with Ki of 1 nM and 1.5 nM, respectively.
In vitro activity:
While there was little difference between the two enantiomers of 25, the (S)-enantiomer of 22 (22b, A-966492) showed superior potency in both PARP enzyme and cellular assays as compared to the respective (R)-enantiomer (22a), highlighted by the 1 nM Ki and EC50 values that exhibited by 22b. This is one of the most potent PARP inhibitors identified to date.
Reference: J Med Chem. 2010 Apr 22;53(8):3142-53. https://pubmed.ncbi.nlm.nih.gov/20337371/
In vivo activity:
Because of a superior profile in the B16 model, 22b (A-966492) was characterized further in vivo. Plasma and tumor levels of 22b were assessed after 5 days of oral dosing in a separate B16F10 study using a 25 mg/kg/day, bid dose of 22b in combination with TMZ (50 mg/kg/day, qd). Significant distribution of 22b to the tumor was observed 6 h after the final dose, with a concentration of 21 μg/mL in the tumor vs 0.38 μg/mL in the plasma. Similar concentrations were obtained when 22b was dosed alone (17.2 vs 0.22 μg/mL).
Reference: J Med Chem. 2010 Apr 22;53(8):3142-53. https://pubmed.ncbi.nlm.nih.gov/20337371/
|
Solvent |
mg/mL |
mM |
| Solubility |
| DMSO |
82.0 |
252.81 |
Note: There can be variations in solubility for the same chemical from different vendors or different batches from the same vendor. The following factors can affect the solubility of the same chemical: solvent used for crystallization, residual solvent content, polymorphism, salt versus free form, degree of hydration, solvent temperature. Please use the solubility data as a reference only. Warming and sonication will facilitate dissolving. Still have questions? Please contact our Technical Support scientists.
Preparing Stock Solutions
The following data is based on the
product
molecular weight
324.35
Batch specific molecular weights may vary
from batch to batch
due to the degree of hydration, which will
affect the solvent
volumes required to prepare stock solutions.
| Concentration / Solvent Volume / Mass |
1 mg |
5 mg |
10 mg |
| 1 mM |
1.15 mL |
5.76 mL |
11.51 mL |
| 5 mM |
0.23 mL |
1.15 mL |
2.3 mL |
| 10 mM |
0.12 mL |
0.58 mL |
1.15 mL |
| 50 mM |
0.02 mL |
0.12 mL |
0.23 mL |
Formulation protocol:
1. Penning TD, Zhu GD, Gong J, Thomas S, Gandhi VB, Liu X, Shi Y, Klinghofer V, Johnson EF, Park CH, Fry EH, Donawho CK, Frost DJ, Buchanan FG, Bukofzer GT, Rodriguez LE, Bontcheva-Diaz V, Bouska JJ, Osterling DJ, Olson AM, Marsh KC, Luo Y, Giranda VL. Optimization of phenyl-substituted benzimidazole carboxamide poly(ADP-ribose) polymerase inhibitors: identification of (S)-2-(2-fluoro-4-(pyrrolidin-2-yl)phenyl)-1H-benzimidazole-4-carboxamide (A-966492), a highly potent and efficacious inhibitor. J Med Chem. 2010 Apr 22;53(8):3142-53. doi: 10.1021/jm901775y. PMID: 20337371.
In vitro protocol:
1. Penning TD, Zhu GD, Gong J, Thomas S, Gandhi VB, Liu X, Shi Y, Klinghofer V, Johnson EF, Park CH, Fry EH, Donawho CK, Frost DJ, Buchanan FG, Bukofzer GT, Rodriguez LE, Bontcheva-Diaz V, Bouska JJ, Osterling DJ, Olson AM, Marsh KC, Luo Y, Giranda VL. Optimization of phenyl-substituted benzimidazole carboxamide poly(ADP-ribose) polymerase inhibitors: identification of (S)-2-(2-fluoro-4-(pyrrolidin-2-yl)phenyl)-1H-benzimidazole-4-carboxamide (A-966492), a highly potent and efficacious inhibitor. J Med Chem. 2010 Apr 22;53(8):3142-53. doi: 10.1021/jm901775y. PMID: 20337371.
In vivo protocol:
1. Penning TD, Zhu GD, Gong J, Thomas S, Gandhi VB, Liu X, Shi Y, Klinghofer V, Johnson EF, Park CH, Fry EH, Donawho CK, Frost DJ, Buchanan FG, Bukofzer GT, Rodriguez LE, Bontcheva-Diaz V, Bouska JJ, Osterling DJ, Olson AM, Marsh KC, Luo Y, Giranda VL. Optimization of phenyl-substituted benzimidazole carboxamide poly(ADP-ribose) polymerase inhibitors: identification of (S)-2-(2-fluoro-4-(pyrrolidin-2-yl)phenyl)-1H-benzimidazole-4-carboxamide (A-966492), a highly potent and efficacious inhibitor. J Med Chem. 2010 Apr 22;53(8):3142-53. doi: 10.1021/jm901775y. PMID: 20337371.
1: Koosha F, Neshasteh-Riz A, Takavar A, Eyvazzadeh N, Mazaheri Z, Eynali S, Mousavi M. The combination of A-966492 and Topotecan for effective radiosensitization on glioblastoma spheroids. Biochem Biophys Res Commun. 2017 Sep 30;491(4):1092-1097. doi: 10.1016/j.bbrc.2017.08.018. Epub 2017 Aug 7. PMID: 28797568.
2: Koosha F, Eynali S, Eyvazzadeh N, Kamalabadi MA. The effect of iodine-131 beta-particles in combination with A-966492 and Topotecan on radio-sensitization of glioblastoma: An in-vitro study. Appl Radiat Isot. 2021 Nov;177:109904. doi: 10.1016/j.apradiso.2021.109904. Epub 2021 Aug 24. PMID: 34454340.
3: Penning TD, Zhu GD, Gong J, Thomas S, Gandhi VB, Liu X, Shi Y, Klinghofer V, Johnson EF, Park CH, Fry EH, Donawho CK, Frost DJ, Buchanan FG, Bukofzer GT, Rodriguez LE, Bontcheva-Diaz V, Bouska JJ, Osterling DJ, Olson AM, Marsh KC, Luo Y, Giranda VL. Optimization of phenyl-substituted benzimidazole carboxamide poly(ADP-ribose) polymerase inhibitors: identification of (S)-2-(2-fluoro-4-(pyrrolidin-2-yl)phenyl)-1H-benzimidazole-4-carboxamide (A-966492), a highly potent and efficacious inhibitor. J Med Chem. 2010 Apr 22;53(8):3142-53. doi: 10.1021/jm901775y. PMID: 20337371.
4: Rudolph J, Roberts G, Luger K. Histone Parylation factor 1 contributes to the inhibition of PARP1 by cancer drugs. Nat Commun. 2021 Feb 2;12(1):736. doi: 10.1038/s41467-021-20998-8. PMID: 33531508; PMCID: PMC7854685.
