Structure-guided design of aminopyrimidine amides as potent, selective inhibitors of lymphocyte specific kinase: synthesis, structure-activity relationships, and inhibition of in vivo T cell activation.
The lymphocyte-specific kinase (Lck), a member of the Src family of cytoplasmic tyrosine kinases, is expressed in T cells and natural killer (NK) cells. Genetic evidence, including knockout mice and human mutations, demonstrates that Lck kinase activity is critical for normal T cell development, activation, and signaling. Selective inhibition of Lck is expected to offer a new therapy for the treatment of T-cell-mediated autoimmune and inflammatory disease. With the aid of X-ray structure-based analysis, aminopyrimidine amides 2 and 3 were designed from aminoquinazolines 1, which had previously been demonstrated to exhibit potent inhibition of Lck and T cell proliferation. In this report, we describe the synthesis and structure-activity relationships of a series of novel aminopyrimidine amides 3 possessing improved cellular potency and selectivity profiles relative to their aminoquinazoline predecessors 1. Orally bioavailable compound 13b inhibited the anti-CD3-induced production of interleukin-2 (IL-2) in mice in a dose-dependent manner (ED 50 = 9.4 mg/kg).
DiMauro
Erin F
EF
Department of Medicinal Chemistry, Amgen Inc., One Kendall Square, Cambridge, MA 02139, USA. edimauro@amgen.com
Newcomb
John
J
Nunes
Joseph J
JJ
Bemis
Jean E
JE
Boucher
Christina
C
Chai
Lilly
L
Chaffee
Stuart C
SC
Deak
Holly L
HL
Epstein
Linda F
LF
Faust
Ted
T
Gallant
Paul
P
Gore
Anu
A
Gu
Yan
Y
Henkle
Brad
B
Hsieh
Faye
F
Huang
Xin
X
Kim
Joseph L
JL
Lee
Josie H
JH
Martin
Matthew W
MW
McGowan
David C
DC
Metz
Daniela
D
Mohn
Deanna
D
Morgenstern
Kurt A
KA
Oliveira-dos-Santos
Antonio
A
Patel
Vinod F
VF
Powers
David
D
Rose
Paul E
PE
Schneider
Stephen
S
Tomlinson
Susan A
SA
Tudor
Yan-Yan
YY
Turci
Susan M
SM
Welcher
Andrew A
AA
Zhao
Huilin
H
Zhu
Li
L
Zhu
Xiaotian
X
D000284:Administration, Oral; D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D006801:Humans; D007376:Interleukin-2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D007694:Killer Cells, Natural / Q000187:drug effects / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000037:antagonists & inhibitors*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D008958:Models, Molecular; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013601:T-Lymphocytes / Q000187:drug effects* / Q000378:metabolism
D000577:Amides; D007376:Interleukin-2; D008070:Lipopolysaccharides; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck)