《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》 was written by 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.. Application of 161489-05-0 And the article was included in Journal of Medicinal Chemistry on April 12 ,2012. The article conveys some information:
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 anal. of the spirohydantoins. This rapid and directed SAR exploration has resulted in the first reported examples of hydantoin derivatives with good PK in preclin. species. Potassium channel off-target activity (hERG) was successfully eliminated through the systematic introduction of acidic functionality to the mol. structure. Undesired upregulation of alanine aminotransferase (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 preclin. species. This profile deems spirohydantoins as attractive short-acting PHDi inhibitors with the potential for treatment of anemia. The results came from multiple reactions, including the reaction of 4-Iodo-6-methoxypyrimidine(cas: 161489-05-0Application of 161489-05-0)
4-Iodo-6-methoxypyrimidine(cas: 161489-05-0) is one of organic iodides. The carbon-iodine bond is weaker than other carbon-halogen bonds due to the poor electronegative nature of the iodine atom. In general, organic iodides are light-sensitive and turn yellow during storage, owing to the formation of iodine. Organic iodides can be alkyl, alkenyl, or alkynyl, and all of them are very reactive toward with many kinds of nucleophiles.Application of 161489-05-0
Referemce:
Iodide – Wikipedia,
Iodide – an overview | ScienceDirect Topics – ScienceDirect.com