Structure-based design, synthesis, and SAR evaluation of a new series of 8-hydroxyquinolines as HIF-1alpha prolyl hydroxylase inhibitors.
A new series of potent 8-hydroxyquinolines was designed based on the newly resolved X-ray crystal structure of EGLN-1. Both alkyl and aryl 8-hydroxyquinoline-7-carboxyamides were good HIF-1alpha prolyl hydroxylase (EGLN) inhibitors. In subsequent VEGF induction assays, these exhibited potent VEGF activity. In addition, this class of compounds did show the ability to stabilize HIF-1alpha.
Warshakoon
Namal C
NC
Drug Discovery Division, Procter and Gamble Pharmaceuticals Inc., 8700 Mason-Montgomery Road, Mason, OH 45040, USA. Warshakoon.nc@pg.com
Wu
Shengde
S
Boyer
Angelique
A
Kawamoto
Richard
R
Sheville
Justin
J
Renock
Sean
S
Xu
Kevin
K
Pokross
Matthew
M
Zhou
Songtao
S
Winter
Carol
C
Walter
Richard
R
Mekel
Marlene
M
Evdokimov
Artem G
AG
D015195:Drug Design; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases; D015125:Oxyquinoline / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011393:Procollagen-Proline Dioxygenase / Q000037:antagonists & inhibitors* / Q000737:chemistry; D013329:Structure-Activity Relationship
D015125:Oxyquinoline; C490190:EGLN1 protein, human; D011393:Procollagen-Proline Dioxygenase; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases