Design and synthesis of a series of novel pyrazolopyridines as HIF-1alpha prolyl hydroxylase inhibitors.
Recently resolved X-ray crystal structure of HIF-1alpha prolyl hydroxylase was used to design and develop a novel series of pyrazolopyridines as potent HIF-1alpha prolyl hydroxylase inhibitors. The activity of these compounds was determined in a human EGLN-1 assay. Structure-based design aided in optimizing the potency of the initial lead (2, IC(50) of 11 microM) to a potent (11l, 190 nM) EGLN-1 inhibitor. Several of these analogs were potent VEGF inducers in a cell-based assay. These pyrazolopyridines were also effective in stabilizing HIF-1alpha.
Warshakoon
Namal C
NC
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
Renock
Sean
S
Xu
Kevin
K
Pokross
Matthew
M
Evdokimov
Artem G
AG
Zhou
Songtao
S
Winter
Carol
C
Walter
Richard
R
Mekel
Marlene
M
D002460:Cell Line; D015195:Drug Design; D006801:Humans; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases; D011393:Procollagen-Proline Dioxygenase / Q000037:antagonists & inhibitors*; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000494:pharmacology*; D011725:Pyridines / Q000138:chemical synthesis* / Q000494:pharmacology*
D011720:Pyrazoles; D011725:Pyridines; C118531:pyrazolopyridine; C490190:EGLN1 protein, human; D011393:Procollagen-Proline Dioxygenase; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases