title: Optimization of a series of 4,6-bis-anilino-1H-pyrrolo[2,3-d]pyrimidine inhibitors of IGF-1R: elimination of an acid-mediated decomposition pathway.
abstract: Initial evaluation of a series 4,6-bis-anilino-1H-pyrrolo[2,3-d]pyrimidines revealed a C(1') carboxamide was preferred for sub-micromolar in vitro potency against IGF-1R. Subsequent solution stability studies with 1 revealed a susceptibility toward acid-induced intramolecular cyclization with the C(1') carboxamide. Herein, we describe several successful approaches toward generating both potent and acid-stable inhibitors of IGF-1R within the 4,6-bis-anilino-1H-pyrrolo[2,3-d]pyrimidine template.
authors.affiliation: GlaxoSmithKline, Oncology R&D, 5 Moore Drive, PO Box 13398, Research Triangle Park, NC 27709-3398, USA.
authors.forename: Stanley D
authors.initials: SD
authors.lastname: Chamberlain
authors.forename: Anikó M
authors.initials: AM
authors.lastname: Redman
authors.forename: Samarjit
authors.initials: S
authors.lastname: Patnaik
authors.forename: Keith
authors.initials: K
authors.lastname: Brickhouse
authors.forename: Yen-Chiat
authors.initials: YC
authors.lastname: Chew
authors.forename: Felix
authors.initials: F
authors.lastname: Deanda
authors.forename: Roseanne
authors.initials: R
authors.lastname: Gerding
authors.forename: Huangshu
authors.initials: H
authors.lastname: Lei
authors.forename: Ganesh
authors.initials: G
authors.lastname: Moorthy
authors.forename: Mark
authors.initials: M
authors.lastname: Patrick
authors.forename: Kirk L
authors.initials: KL
authors.lastname: Stevens
authors.forename: Joseph W
authors.initials: JW
authors.lastname: Wilson
authors.forename: J
authors.initials: J
authors.lastname: Brad Shotwell
mesh_terms: D000143:Acids / Q000737:chemistry*; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D011743:Pyrimidines / Q000737:chemistry / Q000494:pharmacology*; D011758:Pyrroles / Q000737:chemistry / Q000494:pharmacology*; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors*
chemical_list: C538706:4,6-bis-anilino-1H-pyrrolo(2,3-d)pyrimidine; D000143:Acids; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011758:Pyrroles; D017526:Receptor, IGF Type 1