Proline isosteres in a series of 2,4-disubstituted pyrrolo[1,2-f][1,2,4]triazine inhibitors of IGF-1R kinase and IR kinase.
Pyrrolidine, pyrrolidinone, carbocyclic, and acyclic groups were used as isosteric proline replacements in a series of insulin-like growth factor I receptor kinase/insulin receptor kinase inhibitors. Examples that were similar in potency to proline-containing reference compounds were shown to project a key fluoropyridine amide into a common space, while less potent compounds were not able to do so for reasons of stereochemistry or structural rigidity.
Sampognaro
Anthony J
AJ
Department of Discovery Chemistry, Bristol-Myers Squibb Research and Development, Princeton, NJ 08543-5400, USA. anthony.sampognaro@bms.com
Wittman
Mark D
MD
Carboni
Joan M
JM
Chang
Chiehying
C
Greer
Ann F
AF
Hurlburt
Warren W
WW
Sack
John S
JS
Vyas
Dolatrai M
DM
D008958:Models, Molecular; D011392:Proline / Q000737:chemistry*; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors*; D011972:Receptor, Insulin / Q000037:antagonists & inhibitors*; D014227:Triazines / Q000737:chemistry* / Q000494:pharmacology
D047428:Protein Kinase Inhibitors; D014227:Triazines; D011392:Proline; D017526:Receptor, IGF Type 1; D011972:Receptor, Insulin