title: Design and synthesis of a series of novel pyrazolopyridines as HIF-1alpha prolyl hydroxylase inhibitors.
abstract: 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.
authors.affiliation: Procter and Gamble Pharmaceuticals Inc, 8700 Mason-Montgomery road, Mason, OH 45040, USA. Warshakoon.nc@pg.com
authors.forename: Namal C
authors.initials: NC
authors.lastname: Warshakoon
authors.forename: Shengde
authors.initials: S
authors.lastname: Wu
authors.forename: Angelique
authors.initials: A
authors.lastname: Boyer
authors.forename: Richard
authors.initials: R
authors.lastname: Kawamoto
authors.forename: Sean
authors.initials: S
authors.lastname: Renock
authors.forename: Kevin
authors.initials: K
authors.lastname: Xu
authors.forename: Matthew
authors.initials: M
authors.lastname: Pokross
authors.forename: Artem G
authors.initials: AG
authors.lastname: Evdokimov
authors.forename: Songtao
authors.initials: S
authors.lastname: Zhou
authors.forename: Carol
authors.initials: C
authors.lastname: Winter
authors.forename: Richard
authors.initials: R
authors.lastname: Walter
authors.forename: Marlene
authors.initials: M
authors.lastname: Mekel
mesh_terms: 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*
chemical_list: D011720:Pyrazoles; D011725:Pyridines; C118531:pyrazolopyridine; C490190:EGLN1 protein, human; D011393:Procollagen-Proline Dioxygenase; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases