title: Discovery of aminoquinazolines as potent, orally bioavailable inhibitors of Lck: synthesis, SAR, and in vivo anti-inflammatory activity.
abstract: 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.
authors.affiliation: Department of Medicinal Chemistry, Amgen, Inc., Cambridge, Massachusetts 02139, USA. edimauro@amgen.com
authors.forename: Erin F
authors.initials: EF
authors.lastname: DiMauro
authors.forename: John
authors.initials: J
authors.lastname: Newcomb
authors.forename: Joseph J
authors.initials: JJ
authors.lastname: Nunes
authors.forename: Jean E
authors.initials: JE
authors.lastname: Bemis
authors.forename: Christina
authors.initials: C
authors.lastname: Boucher
authors.forename: John L
authors.initials: JL
authors.lastname: Buchanan
authors.forename: William H
authors.initials: WH
authors.lastname: Buckner
authors.forename: Victor J
authors.initials: VJ
authors.lastname: Cee
authors.forename: Lilly
authors.initials: L
authors.lastname: Chai
authors.forename: Holly L
authors.initials: HL
authors.lastname: Deak
authors.forename: Linda F
authors.initials: LF
authors.lastname: Epstein
authors.forename: Ted
authors.initials: T
authors.lastname: Faust
authors.forename: Paul
authors.initials: P
authors.lastname: Gallant
authors.forename: Stephanie D
authors.initials: SD
authors.lastname: Geuns-Meyer
authors.forename: Anu
authors.initials: A
authors.lastname: Gore
authors.forename: Yan
authors.initials: Y
authors.lastname: Gu
authors.forename: Brad
authors.initials: B
authors.lastname: Henkle
authors.forename: Brian L
authors.initials: BL
authors.lastname: Hodous
authors.forename: Faye
authors.initials: F
authors.lastname: Hsieh
authors.forename: Xin
authors.initials: X
authors.lastname: Huang
authors.forename: Joseph L
authors.initials: JL
authors.lastname: Kim
authors.forename: Josie H
authors.initials: JH
authors.lastname: Lee
authors.forename: Matthew W
authors.initials: MW
authors.lastname: Martin
authors.forename: Craig E
authors.initials: CE
authors.lastname: Masse
authors.forename: David C
authors.initials: DC
authors.lastname: McGowan
authors.forename: Daniela
authors.initials: D
authors.lastname: Metz
authors.forename: Deanna
authors.initials: D
authors.lastname: Mohn
authors.forename: Kurt A
authors.initials: KA
authors.lastname: Morgenstern
authors.forename: Antonio
authors.initials: A
authors.lastname: Oliveira-dos-Santos
authors.forename: Vinod F
authors.initials: VF
authors.lastname: Patel
authors.forename: David
authors.initials: D
authors.lastname: Powers
authors.forename: Paul E
authors.initials: PE
authors.lastname: Rose
authors.forename: Stephen
authors.initials: S
authors.lastname: Schneider
authors.forename: Susan A
authors.initials: SA
authors.lastname: Tomlinson
authors.forename: Yan-Yan
authors.initials: YY
authors.lastname: Tudor
authors.forename: Susan M
authors.initials: SM
authors.lastname: Turci
authors.forename: Andrew A
authors.initials: AA
authors.lastname: Welcher
authors.forename: Ryan D
authors.initials: RD
authors.lastname: White
authors.forename: Huilin
authors.initials: H
authors.lastname: Zhao
authors.forename: Li
authors.initials: L
authors.lastname: Zhu
authors.forename: Xiaotian
authors.initials: X
authors.lastname: Zhu
mesh_terms: 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
chemical_list: 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)