Synthesis and biological evaluation of novel (4 or 5-aryl)pyrazolyl-indoles as inhibitors of interleukin-2 inducible T-cell kinase (ITK).
Interleukin-2 inducible T-cell kinase (ITK) is one of five kinases that belong to the Tec kinase family that plays an important role in T-cell and mast cell signaling. Various reports point to a role of ITK in the treatment of allergic asthma. For example, it was shown that mice lacking ITK have reduced airway hyperresponsiveness, inflammation and tracheal responses in an allergic asthma model. In this article, we disclose novel ITK inhibitors based on (4 or 5-aryl)pyrazolyl-indole scaffold that were also found to be selective for ITK over other kinases like IRK, CDK2, GSK3ss and PKA.
Velankar
Avdhoot D
AD
Global Discovery, Nycomed Pharma Pvt. Ltd, Andheri (East), Mumbai, Maharashtra, India. avdhoot.velankar@nycomed.com
Quintini
Gianluca
G
Prabhu
Arati
A
Weber
Alexander
A
Hunaeus
Gundula
G
Voland
Britta
B
Wuest
Monika
M
Orjeda
Christian
C
Harel
Dipak
D
Varghese
Shaji
S
Gore
Vikas
V
Patil
Meenal
M
Gayke
Deepak
D
Herdemann
Matthias
M
Heit
Isabelle
I
Zaliani
Andrea
A
D000818:Animals; D001249:Asthma / Q000188:drug therapy; D001665:Binding Sites; D003198:Computer Simulation; D004195:Disease Models, Animal; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000627:therapeutic use; D051379:Mice; D008958:Models, Molecular; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000627:therapeutic use; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
D007211:Indoles; D047428:Protein Kinase Inhibitors; D011505:Protein-Tyrosine Kinases; C080813:emt protein-tyrosine kinase