Discovery of aminoquinazolines as potent, orally bioavailable inhibitors of Lck: synthesis, SAR, and in vivo anti-inflammatory activity.
The lymphocyte-specific kinase (Lck) is a cytoplasmic tyrosine kinase of the Src family expressed in T cells and natural killer (NK) cells. Genetic evidence in both mice and humans demonstrates that Lck kinase activity is critical for signaling mediated by the T cell receptor (TCR), which leads to normal T cell development and activation. Selective inhibition of Lck is expected to offer a new therapy for the treatment of T-cell-mediated autoimmune and inflammatory disease. Screening of our kinase-preferred collection identified aminoquinazoline 1 as a potent, nonselective inhibitor of Lck and T cell proliferation. In this report, we describe the synthesis and structure-activity relationships of a series of novel aminoquinazolines possessing in vitro mechanism-based potency. Optimized, orally bioavailable compounds 32 and 47 exhibit anti-inflammatory activity (ED(50) of 22 and 11 mg/kg, respectively) in the anti-CD3-induced production of interleukin-2 (IL-2) in mice.
DiMauro
Erin F
EF
Department of Medicinal Chemistry, Amgen, Inc., Cambridge, Massachusetts 02139, USA. edimauro@amgen.com
Newcomb
John
J
Nunes
Joseph J
JJ
Bemis
Jean E
JE
Boucher
Christina
C
Buchanan
John L
JL
Buckner
William H
WH
Cee
Victor J
VJ
Chai
Lilly
L
Deak
Holly L
HL
Epstein
Linda F
LF
Faust
Ted
T
Gallant
Paul
P
Geuns-Meyer
Stephanie D
SD
Gore
Anu
A
Gu
Yan
Y
Henkle
Brad
B
Hodous
Brian L
BL
Hsieh
Faye
F
Huang
Xin
X
Kim
Joseph L
JL
Lee
Josie H
JH
Martin
Matthew W
MW
Masse
Craig E
CE
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
White
Ryan D
RD
Zhao
Huilin
H
Zhu
Li
L
Zhu
Xiaotian
X
D000284:Administration, Oral; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001549:Benzamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001682:Biological Availability; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D007376:Interleukin-2 / Q000096:biosynthesis; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000037:antagonists & inhibitors*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008958:Models, Molecular; D011799:Quinazolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
C514170:4-methyl-3-(2-(2-morpholinoethylamino)quinazolin-6-yl)-N-(3-(trifluoromethyl)phenyl)benzamide; C514169:4-methyl-3-(2-(methylamino)quinazolin-6-yl)-N-(2-(1-methylpiperidin-4-yloxy)-5-(trifluoromethyl)phenyl)benzamide; D000894:Anti-Inflammatory Agents, Non-Steroidal; D001549:Benzamides; D007376:Interleukin-2; D011799:Quinazolines; D014409:Tumor Necrosis Factor-alpha; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck)