title: Imidazo[1,5-a]quinoxalines as irreversible BTK inhibitors for the treatment of rheumatoid arthritis.
abstract: Imidazo[1,5-a]quinoxalines were synthesized that function as irreversible Bruton's tyrosine kinase (BTK) inhibitors. The syntheses and SAR of this series of compounds are presented as well as the X-ray crystal structure of the lead compound 36 in complex with a gate-keeper variant of ITK enzyme. The lead compound showed good in vivo efficacy in preclinical RA models.
authors.affiliation: Medicinal Chemistry, Pfizer, 200 Cambridge Park Drive, Cambridge, MA 02140, United States. khkim87@hotmail.com
authors.forename: Kyung-Hee
authors.initials: KH
authors.lastname: Kim
authors.forename: Andreas
authors.initials: A
authors.lastname: Maderna
authors.forename: Mark E
authors.initials: ME
authors.lastname: Schnute
authors.forename: Martin
authors.initials: M
authors.lastname: Hegen
authors.forename: Shashi
authors.initials: S
authors.lastname: Mohan
authors.forename: Joy
authors.initials: J
authors.lastname: Miyashiro
authors.forename: Laura
authors.initials: L
authors.lastname: Lin
authors.forename: Evelyn
authors.initials: E
authors.lastname: Li
authors.forename: Sean
authors.initials: S
authors.lastname: Keegan
authors.forename: Jennifer
authors.initials: J
authors.lastname: Lussier
authors.forename: Christopher
authors.initials: C
authors.lastname: Wrocklage
authors.forename: Cheryl L
authors.initials: CL
authors.lastname: Nickerson-Nutter
authors.forename: Arthur J
authors.initials: AJ
authors.lastname: Wittwer
authors.forename: Holly
authors.initials: H
authors.lastname: Soutter
authors.forename: Nicole
authors.initials: N
authors.lastname: Caspers
authors.forename: Seungil
authors.initials: S
authors.lastname: Han
authors.forename: Ravi
authors.initials: R
authors.lastname: Kurumbail
authors.forename: Kyri
authors.initials: K
authors.lastname: Dunussi-Joannopoulos
authors.forename: John
authors.initials: J
authors.lastname: Douhan
authors.forename: Allan
authors.initials: A
authors.lastname: Wissner
mesh_terms: D000077329:Agammaglobulinaemia Tyrosine Kinase; D001172:Arthritis, Rheumatoid / Q000188:drug therapy*; D018360:Crystallography, X-Ray; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011810:Quinoxalines / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D047428:Protein Kinase Inhibitors; D011810:Quinoxalines; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625949:BTK protein, human