Scaffold oriented synthesis. Part 2: Design, synthesis and biological evaluation of pyrimido-diazepines as receptor tyrosine kinase inhibitors.
We report the discovery of the pyrimido-diazepine scaffolds as novel adenine mimics. Structure-based design led to the discovery of analogs with potent inhibitory activity against receptor tyrosine kinases, such as KDR, Flt3 and c-Kit. Compound 14 exhibited low nanomolar KDR enzymatic and cellular potencies (IC(50)=9 and 52 nM, respectively).
Gracias
Vijaya
V
Global Pharmaceutical Research and Development, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, IL 60044, USA.
Ji
Zhiqin
Z
Akritopoulou-Zanze
Irini
I
Abad-Zapatero
Cele
C
Huth
Jeffrey R
JR
Song
Danying
D
Hajduk
Philip J
PJ
Johnson
Eric F
EF
Glaser
Keith B
KB
Marcotte
Patrick A
PA
Pease
Lori
L
Soni
Nirupama B
NB
Stewart
Kent D
KD
Davidsen
Steven K
SK
Michaelides
Michael R
MR
Djuric
Stevan W
SW
D016475:3T3 Cells; D000818:Animals; D001381:Azepines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D015195:Drug Design; D006860:Hydrogen Bonding; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D011743:Pyrimidines / Q000737:chemistry*; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D013329:Structure-Activity Relationship
D001381:Azepines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D020794:Receptor Protein-Tyrosine Kinases; C030986:pyrimidine