Design and synthesis of substituted pyridine derivatives as HIF-1alpha prolyl hydroxylase inhibitors.
Structure-guided de novo drug design led to the identification of a novel series of substituted pyridine derivatives as HIF-1alpha prolyl hydroxylase inhibitors. Pyridine carboxyamide derivatives bearing a substituted aryl group at the 5-position of the pyridine ring show appreciable activity, while constraining the side chain by placing a pyrazole carboxylic acid generated a potent lead series with consistent activity against EGLN-1.
Warshakoon
Namal C
NC
Lead Discovery, Procter and Gamble Pharmaceuticals, 8700 Mason-Montgomery Rd, Mason, OH 45040, USA. Warshakoon.nc@pg.com
Wu
Shengde
S
Boyer
Angelique
A
Kawamoto
Richard
R
Sheville
Justin
J
Bhatt
Ritu Tiku
RT
Renock
Sean
S
Xu
Kevin
K
Pokross
Matthew
M
Zhou
Songtao
S
Walter
Richard
R
Mekel
Marlene
M
Evdokimov
Artem G
AG
East
Stephen
S
D015195:Drug Design; D006801:Humans; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases; D011393:Procollagen-Proline Dioxygenase / Q000037:antagonists & inhibitors*; D011725:Pyridines / Q000138:chemical synthesis* / Q000494:pharmacology*
D011725:Pyridines; C490190:EGLN1 protein, human; D011393:Procollagen-Proline Dioxygenase; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases