2-Aminopyrazolo[1,5-a]pyrimidines as potent and selective inhibitors of JAK2.
Constitutive activation of the EPO/JAK2 signaling cascade has recently been implicated in a variety of myeloproliferative disorders including polycythemia vera, essential thrombocythemia and myelofibrosis. In an effort to uncover therapeutic potential of blocking the EPO/JAK2 signaling cascade, we sought to discover selective inhibitors that block the kinase activity of JAK2. Herein, we describe the discovery and structure based optimization of a novel series of 2-amino-pyrazolo[1,5-a]pyrimidines that exhibit potent inhibition of JAK2.
Ledeboer
Mark W
MW
Vertex Pharmaceuticals Inc, Cambridge, MA 02139-4242, United States. mark_ledeboer@vrtx.com
Pierce
Albert C
AC
Duffy
John P
JP
Gao
Huai
H
Messersmith
David
D
Salituro
Francesco G
FG
Nanthakumar
Suganthini
S
Come
Jon
J
Zuccola
Harmon J
HJ
Swenson
Lora
L
Shlyakter
Dina
D
Mahajan
Sudipta
S
Hoock
Thomas
T
Fan
Bin
B
Tsai
Wan-Jung
WJ
Kolaczkowski
Elaine
E
Carrier
Scott
S
Hogan
James K
JK
Zessis
Richard
R
Pazhanisamy
S
S
Bennani
Youssef L
YL
D018360:Crystallography, X-Ray; D055808:Drug Discovery; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors*; D008958:Models, Molecular; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; D053614:Janus Kinase 2