1254036-66-2 Usage
Uses
rel-N-[5-[4-[5-[[(2R,6S)-2,6-Dimethyl-4-morpholinyl]methyl]-2-oxazolyl]-1H-indazol-6-yl]-2-methoxy-3-pyridinyl]methanesulfonamide is a selective PI3Kδ inhibitor for the treatment of respiratory disease (1,2).
Biological Activity
pki: 10.1gsk2292767 is a potent and selective pi3kδ inhibitor.phosphoinositide 3-kinase δ (pi3kδ), a lipid kinase belonging to the class 1 pi3k family with the closely homologous isoforms α and β, catalyzes the phosphorylation of phosphatidylinositol 4,5-bisphosphate, triggering various downstream biological events suvch as cell growth, proliferation, differentiation, and survival.
in vitro
gsk2292767 was found to be greater than 100-fold selective against a panel of in-house kinases and in the millipore panel. moreover, gsk2292767 could inhibit both ifnγ and il-2 production in a concentration-dependent manner in a human lung parenchyma assay, with pic50s of 8.7 and 8.5, respectively [1].
in vivo
in a rat pk study, the in vivo clearance for gsk2292767 was significantly higher than that for its analog gsk2269557. the oral bioavailability was also low (f < 2%), which was consistent with the data observed for gsk2269557. in a rabbit cardiac ventricular wedge assay, no effect on qt interval, tpe, or qrs and no significant risk of tdp arrhythmias was observed for gsk2292767 over the concentration range tested, thus indicating gsk2292767 could successfully mitigate the risk associated with gsk2269557. moreover, gsk2292767 was found to protect against eosinophil recruitment with an ed50 of 35 μg/kg in the brown norway rat acute ova model, which was similar to gsk2269557 [1].
references
[1] down k et al. optimization of novel indazoles as highly potent and selective inhibitors of phosphoinositide 3-kinase δ for the treatment of respiratory disease. j med chem. 2015 sep 24;58(18):7381-99.
Check Digit Verification of cas no
The CAS Registry Mumber 1254036-66-2 includes 10 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 7 digits, 1,2,5,4,0,3 and 6 respectively; the second part has 2 digits, 6 and 6 respectively.
Calculate Digit Verification of CAS Registry Number 1254036-66:
(9*1)+(8*2)+(7*5)+(6*4)+(5*0)+(4*3)+(3*6)+(2*6)+(1*6)=132
132 % 10 = 2
So 1254036-66-2 is a valid CAS Registry Number.
1254036-66-2Relevant articles and documents
Development of Flexible and Scalable Routes to Two Phosphatidinylinositol-3-kinase Delta Inhibitors via a Common Intermediate Approach
Edney, Dean,Hulcoop, David G.,Leahy, John H.,Vernon, Lois E.,Wipperman, Mark D.,Bream, Robert N.,Webb, Michael R.
, p. 368 - 376 (2018/03/22)
This paper describes the discovery and development of a flexible route to two candidate drug molecules by a common intermediate approach. Key reactions include Negishi and Suzuki couplings to form biaryl bonds. Conditions for a Miyaura borylation of heteroaryl bromides were also developed. Heteroaryl trifluoroborates and aryl chlorides were used as coupling partners in the Suzuki reaction, thereby minimizing detrimental side reactions such as protodeboronation and oxidative homocoupling. A complementary set of reaction conditions using pinacolboronates with potassium bifluoride as an additive were also developed and used to make 5 kg of drug substance for use in early-phase clinical trials.
POLYMORPHS AND SALTS OF N- [5- [4- (5- { [(2R,6S) -2, 6 - DIMETHYL - 4 -MORPHOLINYL] METHYL} - 1, 3 - OXAZOL - 2 - YL) - 1H- INDA ZOL-6-YL] -2- (METHYLOXY) - 3 - PYRIDINYL] METHANESULFONAMIDE
-
, (2012/03/27)
The present invention is directed to novel polymorphs and salts of a compound which is an inhibitor of kinase activity.
