Design of potent IGF1-R inhibitors related to bis-azaindoles.
From an azaindole lead, identified in high throughput screen, a series of potent bis-azaindole inhibitors of IGF1-R have been synthesized using rational drug design and SAR based on a in silico binding mode hypothesis. Although the resulting compounds produced the expected improved potency, the model was not validated by the co-crystallization experiments with IGF1-R.
Nemecek
Conception
C
Medicinal Chemistry, Sanofi-Aventis, 13 Quai Jules Guesde, 94300 Vitry-sur-Seine, France.
Metz
William A
WA
Wentzler
Sylvie
S
Ding
Fa-Xiang
FX
Venot
Corinne
C
Souaille
Catherine
C
Dagallier
Anne
A
Maignan
Sébastien
S
Guilloteau
Jean-Pierre
JP
Bernard
François
F
Henry
Alain
A
Grapinet
Sandrine
S
Lesuisse
Dominique
D
D000818:Animals; D001665:Binding Sites; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D007334:Insulin-Like Growth Factor I / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051379:Mice; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D013329:Structure-Activity Relationship
D007211:Indoles; D047428:Protein Kinase Inhibitors; C519530:insulin-like growth factor-1, mouse; D007334:Insulin-Like Growth Factor I