title: Dipeptidyl-quinolone derivatives inhibit hypoxia inducible factor-1α prolyl hydroxylases-1, -2, and -3 with altered selectivity.
abstract: Intracellular levels of the hypoxia-inducible transcription factor (HIF) are regulated under normoxic conditions by prolyl hydroxylases (PHD1, 2, and 3). Treatment of cells with PHD inhibitors stabilizes HIF-1α, eliciting an artificial hypoxic response that includes the transcription of genes involved in erythropoiesis, angiogenesis, and glycolysis. The different in vivo roles of the three PHD isoforms are not yet known, making a PHD-selective inhibitor useful as a biological tool. Although several chemical series of PHD inhibitors have been described, significant isoform selectivity has not been reported. Here we report the synthesis and activity of dipeptidyl analogues derived from a potent but non-selective quinolone scaffold. The compounds were prepared by Pd-catalyzed reductive carbonylation of the 6-iodoquinolone derivative to form the aldehyde directly, which was then attached to a solid support via reductive amination. Amino acids were coupled, and the resulting dipeptidyl-quinolone derivatives were screened, revealing retention of PHD inhibitory activity but an altered PHD1, 2, and 3 selectivity profile. The compounds were found to be ∼10-fold more potent against PHD1 and PHD3 than against PHD2, whereas the specific parent compound had shown no appreciable selectivity among the different PHD isoforms.
authors.affiliation: Chemistry Research & Discovery, Amgen, Inc., One Amgen Center Drive, Thousand Oaks, California 91320, USA.
authors.forename: Justin K
authors.initials: JK
authors.lastname: Murray
authors.forename: Chenera
authors.initials: C
authors.lastname: Balan
authors.forename: Alan M
authors.initials: AM
authors.lastname: Allgeier
authors.forename: Annie
authors.initials: A
authors.lastname: Kasparian
authors.forename: Vellarkad
authors.initials: V
authors.lastname: Viswanadhan
authors.forename: Christopher
authors.initials: C
authors.lastname: Wilde
authors.forename: Jennifer R
authors.initials: JR
authors.lastname: Allen
authors.forename: Sean C
authors.initials: SC
authors.lastname: Yoder
authors.forename: Gloria
authors.initials: G
authors.lastname: Biddlecome
authors.forename: Randall W
authors.initials: RW
authors.lastname: Hungate
authors.forename: Les P
authors.initials: LP
authors.lastname: Miranda
mesh_terms: D020650:Combinatorial Chemistry Techniques; D004151:Dipeptides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D007527:Isoenzymes / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D015394:Molecular Structure; D011393:Procollagen-Proline Dioxygenase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D015363:Quinolones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D004151:Dipeptides; D004791:Enzyme Inhibitors; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007527:Isoenzymes; D015363:Quinolones; D011393:Procollagen-Proline Dioxygenase