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.
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.
Chamberlain
Stanley D
SD
GlaxoSmithKline, Oncology R&D, 5 Moore Drive, PO Box 13398, Research Triangle Park, NC 27709-3398, USA.
Redman
Anikó M
AM
Patnaik
Samarjit
S
Brickhouse
Keith
K
Chew
Yen-Chiat
YC
Deanda
Felix
F
Gerding
Roseanne
R
Lei
Huangshu
H
Moorthy
Ganesh
G
Patrick
Mark
M
Stevens
Kirk L
KL
Wilson
Joseph W
JW
Brad Shotwell
J
J
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*
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