title: 1,3,8-Triazaspiro[4.5]decane-2,4-diones as efficacious pan-inhibitors of hypoxia-inducible factor prolyl hydroxylase 1-3 (HIF PHD1-3) for the treatment of anemia.
abstract: The discovery of 1,3,8-triazaspiro[4.5]decane-2,4-diones (spirohydantoins) as a structural class of pan-inhibitors of the prolyl hydroxylase (PHD) family of enzymes for the treatment of anemia is described. The initial hit class, spirooxindoles, was identified through affinity selection mass spectrometry (AS-MS) and optimized for PHD2 inhibition and optimal PK/PD profile (short-acting PHDi inhibitors). 1,3,8-Triazaspiro[4.5]decane-2,4-diones (spirohydantoins) were optimized as an advanced lead class derived from the original spiroindole hit. A new set of general conditions for C-N coupling, developed using a high-throughput experimentation (HTE) technique, enabled a full SAR analysis of the spirohydantoins. This rapid and directed SAR exploration has resulted in the first reported examples of hydantoin derivatives with good PK in preclinical species. Potassium channel off-target activity (hERG) was successfully eliminated through the systematic introduction of acidic functionality to the molecular structure. Undesired upregulation of alanine aminotransferese (ALT) liver enzymes was mitigated and a robust on-/off-target margin was achieved. Spirohydantoins represent a class of highly efficacious, short-acting PHD1-3 inhibitors causing a robust erythropoietin (EPO) upregulation in vivo in multiple preclinical species. This profile deems spirohydantoins as attractive short-acting PHDi inhibitors with the potential for treatment of anemia.
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, Rahway, New Jersey 07065, USA. petr_vachal@merck.com
authors.forename: Petr
authors.initials: P
authors.lastname: Vachal
authors.forename: Shouwu
authors.initials: S
authors.lastname: Miao
authors.forename: Joan M
authors.initials: JM
authors.lastname: Pierce
authors.forename: Deodial
authors.initials: D
authors.lastname: Guiadeen
authors.forename: Vincent J
authors.initials: VJ
authors.lastname: Colandrea
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Wyvratt
authors.forename: Scott P
authors.initials: SP
authors.lastname: Salowe
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Sonatore
authors.forename: James A
authors.initials: JA
authors.lastname: Milligan
authors.forename: Richard
authors.initials: R
authors.lastname: Hajdu
authors.forename: Anantha
authors.initials: A
authors.lastname: Gollapudi
authors.forename: Carol A
authors.initials: CA
authors.lastname: Keohane
authors.forename: Russell B
authors.initials: RB
authors.lastname: Lingham
authors.forename: Suzanne M
authors.initials: SM
authors.lastname: Mandala
authors.forename: Julie A
authors.initials: JA
authors.lastname: DeMartino
authors.forename: Xinchun
authors.initials: X
authors.lastname: Tong
authors.forename: Michael
authors.initials: M
authors.lastname: Wolff
authors.forename: Dietrich
authors.initials: D
authors.lastname: Steinhuebel
authors.forename: Gerard R
authors.initials: GR
authors.lastname: Kieczykowski
authors.forename: Fred J
authors.initials: FJ
authors.lastname: Fleitz
authors.forename: Kevin
authors.initials: K
authors.lastname: Chapman
authors.forename: John
authors.initials: J
authors.lastname: Athanasopoulos
authors.forename: Gregory
authors.initials: G
authors.lastname: Adam
authors.forename: Can D
authors.initials: CD
authors.lastname: Akyuz
authors.forename: Dhirendra K
authors.initials: DK
authors.lastname: Jena
authors.forename: Jeffrey W
authors.initials: JW
authors.lastname: Lusen
authors.forename: Juncai
authors.initials: J
authors.lastname: Meng
authors.forename: Benjamin D
authors.initials: BD
authors.lastname: Stein
authors.forename: Lei
authors.initials: L
authors.lastname: Xia
authors.forename: Edward C
authors.initials: EC
authors.lastname: Sherer
authors.forename: Jeffrey J
authors.initials: JJ
authors.lastname: Hale
mesh_terms: D000740:Anemia / Q000188:drug therapy*; D000818:Animals; D001372:Aza Compounds / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D004285:Dogs; D000072237:ERG1 Potassium Channel; D004921:Erythropoietin / Q000096:biosynthesis; D051638:Ether-A-Go-Go Potassium Channels / Q000378:metabolism; D057166:High-Throughput Screening Assays; D006801:Humans; D006827:Hydantoins / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D051793:Hypoxia-Inducible Factor 1 / Q000378:metabolism*; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases; D007211:Indoles / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008253:Macaca mulatta; D013058:Mass Spectrometry; D051379:Mice; D008810:Mice, Inbred C57BL; D011393:Procollagen-Proline Dioxygenase / Q000037:antagonists & inhibitors*; D011485:Protein Binding; D051381:Rats; D013141:Spiro Compounds / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D013329:Structure-Activity Relationship; D015854:Up-Regulation
chemical_list: D001372:Aza Compounds; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D006827:Hydantoins; D051793:Hypoxia-Inducible Factor 1; D007211:Indoles; C000606913:KCNH2 protein, human; D013141:Spiro Compounds; D004921:Erythropoietin; C490190:EGLN1 protein, human; D011393:Procollagen-Proline Dioxygenase; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases