title: 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.
abstract: 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).
authors.affiliation: Department of Medicinal Chemistry, Amgen Inc., One Kendall Square, Cambridge, MA 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: Lilly
authors.initials: L
authors.lastname: Chai
authors.forename: Stuart C
authors.initials: SC
authors.lastname: Chaffee
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: 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: 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: 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: 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; 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
chemical_list: D000577:Amides; D007376:Interleukin-2; D008070:Lipopolysaccharides; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck)