183673-70-3Relevant articles and documents
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.
, p. 2945 - 2959 (2012)
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.
CD16A BINDING AGENTS AND USES THEREOF
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Paragraph 00494; 00572; 00577; 00582; 00587; 00593; 00611, (2019/07/20)
Among other things, the present disclosure provides compounds, compositions thereof, and methods of using the same. In some embodiments, compounds of the present disclosure bind to Fc receptors, e.g., CD16a. In some embodiments, compounds of the present disclosure are useful for treating various conditions, disorders or diseases including cancer.
Evaluation of spiropiperidine hydantoins as a novel class of antimalarial agents
Meyers, Marvin J.,Anderson, Elizabeth J.,McNitt, Sarah A.,Krenning, Thomas M.,Singh, Megh,Xu, Jing,Zeng, Wentian,Qin, Limei,Xu, Wanwan,Zhao, Siting,Qin, Li,Eickhoff, Christopher S.,Oliva, Jonathan,Campbell, Mary A.,Arnett, Stacy D.,Prinsen, Michael J.,Griggs, David W.,Ruminski, Peter G.,Goldberg, Daniel E.,Ding, Ke,Liu, Xiaorong,Tu, Zhengchao,Tortorella, Micky D.,Sverdrup, Francis M.,Chen, Xiaoping
, p. 5144 - 5150 (2015/03/30)
Given the rise of parasite resistance to all currently used antimalarial drugs, the identification of novel chemotypes with unique mechanisms of action is of paramount importance. Since Plasmodium expresses a number of aspartic proteases necessary for its survival, we have mined antimalarial datasets for drug-like aspartic protease inhibitors. This effort led to the identification of spiropiperidine hydantoins, bearing similarity to known inhibitors of the human aspartic protease β-secretase (BACE), as new leads for antimalarial drug discovery. Spiropiperidine hydantoins have a dynamic structure-activity relationship profile with positions identified as being tolerant of a variety of substitution patterns as well as a key piperidine N-benzyl phenol pharmacophore. Lead compounds 4e (CWHM-123) and 12k (CWHM-505) are potent antimalarials with IC50 values against Plasmodium falciparum 3D7 of 0.310 μM and 0.099 μM, respectively, and the former features equivalent potency on the chloroquine-resistant Dd2 strain. Remarkably, these compounds do not inhibit human aspartic proteases BACE, cathepsins D and E, or Plasmodium plasmepsins II and IV despite their similarity to known BACE inhibitors. Although the current leads suffer from poor metabolic stability, they do fit into a drug-like chemical property space and provide a new class of potent antimalarial agents for further study.
