Design and synthesis of a series of novel pyrazolopyridines as HIF 1-α prolyl hydroxylase inhibitors
2006; Elsevier BV; Volume: 16; Issue: 21 Linguagem: Inglês
10.1016/j.bmcl.2006.08.017
ISSN1464-3405
AutoresNamal C. Warshakoon, Shengde Wu, Angelique Boyer, Richard M. Kawamoto, Sean Renock, Kevin Xu, Matthew Pokross, A.G. Evdokimov, Songtao Zhou, Carol Winter, Richard Walter, Marlene Mekel,
Tópico(s)Metabolism, Diabetes, and Cancer
ResumoRecently 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.
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