946135-52-0Relevant academic research and scientific papers
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
Vachal, Petr,Miao, Shouwu,Pierce, Joan M.,Guiadeen, Deodial,Colandrea, Vincent J.,Wyvratt, Matthew J.,Salowe, Scott P.,Sonatore, Lisa M.,Milligan, James A.,Hajdu, Richard,Gollapudi, Anantha,Keohane, Carol A.,Lingham, Russell B.,Mandala, Suzanne M.,Demartino, Julie A.,Tong, Xinchun,Wolff, Michael,Steinhuebel, Dietrich,Kieczykowski, Gerard R.,Fleitz, Fred J.,Chapman, Kevin,Athanasopoulos, John,Adam, Gregory,Akyuz, Can D.,Jena, Dhirendra K.,Lusen, Jeffrey W.,Meng, Juncai,Stein, Benjamin D.,Xia, Lei,Sherer, Edward C.,Hale, Jeffrey J.
supporting information; experimental part, p. 2945 - 2959 (2012/05/20)
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.
An efficient synthesis of a spirocyclic oxindole analogue
Teng, Dawei,Zhang, Hongxing,Mendonca
, p. 700 - 706 (2008/02/08)
An efficient, scaleable synthesis approach towards the spirocyclic oxindole analogue 1′-(tert-butoxycarbonyl)-2-oxospiro[indoline-3,4′- piperidine]-5-carboxylic acid (1) is described. The key steps are dianion alkylation and cyclization of ethyl 2-oxindoline-5-carboxylate (4) and demethylation of the resulting spirocyclic oxindole ethyl 1′-methyl-2- oxospiro[indoline-3,4′-piperidine]-5-carboxylate (5). The target compound was obtained in an overall yield of 35 % over eight steps without resorting to chromatographic purification.
