title: Optimization of 2-phenylaminoimidazo[4,5-h]isoquinolin-9-ones: orally active inhibitors of lck kinase.
abstract: The tyrosine kinase p56lck (lck) is essential for T cell activation; thus, inhibitors of lck have potential utility as autoimmune agents. Our initial disclosure of a new class of lck inhibitors based on the phenylaminoimidazoisoquinolin-9-one showed reasonable cellular activity but did not work in vivo upon oral administration. Our current work highlights the further use of rational drug design and molecular modeling to produce a series of lck inhibitors that demonstrate cellular activity below 100 nM and are as efficacious as cyclosporin A in an in vivo mouse model of anti-CD3-induced IL-2 production.
authors.affiliation: Department of Medicinal Chemistry, Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, Ridgefield, Connecticut 06877, USA. dgoldber@rdg.boehringer-ingelheim.com
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Goldberg
authors.forename: Tanja
authors.initials: T
authors.lastname: Butz
authors.forename: Mario G
authors.initials: MG
authors.lastname: Cardozo
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Eckner
authors.forename: Abdelhakim
authors.initials: A
authors.lastname: Hammach
authors.forename: Jessica
authors.initials: J
authors.lastname: Huang
authors.forename: Scott
authors.initials: S
authors.lastname: Jakes
authors.forename: Suresh
authors.initials: S
authors.lastname: Kapadia
authors.forename: Mohammed
authors.initials: M
authors.lastname: Kashem
authors.forename: Susan
authors.initials: S
authors.lastname: Lukas
authors.forename: Tina M
authors.initials: TM
authors.lastname: Morwick
authors.forename: Maret
authors.initials: M
authors.lastname: Panzenbeck
authors.forename: Usha
authors.initials: U
authors.lastname: Patel
authors.forename: Susan
authors.initials: S
authors.lastname: Pav
authors.forename: Gregory W
authors.initials: GW
authors.lastname: Peet
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Peterson
authors.forename: Anthony S
authors.initials: AS
authors.lastname: Prokopowicz
authors.forename: Roger J
authors.initials: RJ
authors.lastname: Snow
authors.forename: Rosemarie
authors.initials: R
authors.lastname: Sellati
authors.forename: Hidenori
authors.initials: H
authors.lastname: Takahashi
authors.forename: Jonathan
authors.initials: J
authors.lastname: Tan
authors.forename: Matt A
authors.initials: MA
authors.lastname: Tschantz
authors.forename: Xiao-Jun
authors.initials: XJ
authors.lastname: Wang
authors.forename: Yong
authors.initials: Y
authors.lastname: Wang
authors.forename: John
authors.initials: J
authors.lastname: Wolak
authors.forename: Pla
authors.initials: P
authors.lastname: Xiong
authors.forename: Neil
authors.initials: N
authors.lastname: Moss
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D001562:Benzimidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D017252:CD3 Complex / Q000276:immunology; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007376:Interleukin-2 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000097:blood; D007546:Isoquinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D019169:Jurkat Cells; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000037:antagonists & inhibitors*; D051379:Mice; D008807:Mice, Inbred BALB C; D008958:Models, Molecular; D008968:Molecular Conformation; D011485:Protein Binding; D013329:Structure-Activity Relationship
chemical_list: D000911:Antibodies, Monoclonal; D001562:Benzimidazoles; D017252:CD3 Complex; D004791:Enzyme Inhibitors; D007166:Immunosuppressive Agents; D007376:Interleukin-2; D007546:Isoquinolines; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck)