title: Structure-based design of novel 2-amino-6-phenyl-pyrimido[5',4':5,6]pyrimido[1,2-a]benzimidazol-5(6H)-ones as potent and orally active inhibitors of lymphocyte specific kinase (Lck): synthesis, SAR, and in vivo anti-inflammatory activity.
abstract: Lck, or lymphocyte specific kinase, is a cytoplasmic tyrosine kinase of the Src family expressed in T-cells and NK cells. Genetic evidence from knockout mice and human mutations demonstrates that Lck kinase activity is critical for T-cell receptor-mediated signaling, leading to normal T-cell development and activation. A small molecule inhibitor of Lck is expected to be useful in the treatment of T-cell-mediated autoimmune and inflammatory disorders and/or organ transplant rejection. In this paper, we describe the structure-guided design, synthesis, structure-activity relationships, and pharmacological characterization of 2-amino-6-phenylpyrimido[5',4':5,6]pyrimido[1,2- a]benzimidazol-5(6 H)-ones, a new class of compounds that are potent inhibitors of Lck. The most promising compound of this series, 6-(2,6-dimethylphenyl)-2-((4-(4-methyl-1-piperazinyl)phenyl)amino)pyrimido[5',4':5,6]pyrimido-[1,2- a]benzimidazol-5(6 H)-one ( 25), exhibits potent inhibition of Lck kinase activity. This activity translates into inhibition of in vitro cell-based assays and in vivo models of T-cell activation and arthritis, respectively.
authors.affiliation: Department of Medicinal Chemistry, Amgen Inc., One Kendall Square, Cambridge, MA 02139, USA. matmarti@amgen.com
authors.forename: Matthew W
authors.initials: MW
authors.lastname: Martin
authors.forename: John
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authors.lastname: Newcomb
authors.forename: Joseph J
authors.initials: JJ
authors.lastname: Nunes
authors.forename: Christina
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authors.forename: Lilly
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authors.forename: Linda F
authors.initials: LF
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authors.forename: Faye
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authors.lastname: Hsieh
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authors.initials: X
authors.lastname: Huang
authors.forename: Joseph L
authors.initials: JL
authors.lastname: Kim
authors.forename: Scot
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authors.lastname: Middleton
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authors.lastname: Morgenstern
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authors.lastname: Oliveira-dos-Santos
authors.forename: Vinod F
authors.initials: VF
authors.lastname: Patel
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authors.lastname: Powers
authors.forename: Paul
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authors.lastname: Rose
authors.forename: Yanyan
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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: Debra
authors.initials: D
authors.lastname: Zack
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
authors.forename: Chiara
authors.initials: C
authors.lastname: Ghiron
authors.forename: Monika
authors.initials: M
authors.lastname: Ermann
authors.forename: David
authors.initials: D
authors.lastname: Johnston
authors.forename: Carl-Gustaf Pierre
authors.initials: CG
authors.lastname: Saluste
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001168:Arthritis / Q000188:drug therapy*; D001562:Benzimidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D018360:Crystallography, X-Ray; D004195:Disease Models, Animal; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D007271:Injections, Intradermal; D007376:Interleukin-2 / Q000378:metabolism; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000037:antagonists & inhibitors*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008958:Models, Molecular; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011744:Pyrimidinones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D011917:Rats, Inbred Lew; D017207:Rats, Sprague-Dawley; D015203:Reproducibility of Results; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D001562:Benzimidazoles; D007376:Interleukin-2; D047428:Protein Kinase Inhibitors; D011744:Pyrimidinones; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck)