title: Design and synthesis of isoquinolines and benzimidazoles as RAF kinase inhibitors.
abstract: RAF kinase plays a critical role in the RAF-MEK-ERK signaling pathway and inhibitors of RAF could be of use for the treatment of various cancer types. We have designed potent RAF-1 inhibitors bearing novel bicyclic heterocycles as key structural elements for the interaction with the hinge region. In both series exploration of the SAR was focussed on the substitution of the phenyl ring, which binds to the induced fit pocket. Overall, it was confirmed that incorporation of lipophilic substituents was needed for potent Raf inhibition and a number of potent analogues were obtained.
authors.affiliation: Merck Serono, Merck KGaA, Frankfurter Straße 250, D-64293 Darmstadt, Germany. hans-peter.buchstaller@merck.de
authors.forename: Hans-Peter
authors.initials: HP
authors.lastname: Buchstaller
authors.forename: Lars
authors.initials: L
authors.lastname: Burgdorf
authors.forename: Dirk
authors.initials: D
authors.lastname: Finsinger
authors.forename: Frank
authors.initials: F
authors.lastname: Stieber
authors.forename: Christian
authors.initials: C
authors.lastname: Sirrenberg
authors.forename: Christiane
authors.initials: C
authors.lastname: Amendt
authors.forename: Matthias
authors.initials: M
authors.lastname: Grell
authors.forename: Frank
authors.initials: F
authors.lastname: Zenke
authors.forename: Mireille
authors.initials: M
authors.lastname: Krier
mesh_terms: D001562:Benzimidazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D001665:Binding Sites; D020134:Catalytic Domain; D003198:Computer Simulation; D015195:Drug Design; D007546:Isoquinolines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015398:Signal Transduction; D013329:Structure-Activity Relationship; D048490:raf Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D001562:Benzimidazoles; D007546:Isoquinolines; D047428:Protein Kinase Inhibitors; D048490:raf Kinases