- 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
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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.
- 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.
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Read Online
- Discovery of Potent Coumarin-Based Kinetic Stabilizers of Amyloidogenic Immunoglobulin Light Chains Using Structure-Based Design
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In immunoglobulin light-chain (LC) amyloidosis, transient unfolding or unfolding and proteolysis enable aggregation of LC proteins, causing potentially fatal organ damage. A drug that kinetically stabilizes LCs could suppress aggregation; however, LC sequences are variable and have no natural ligands, hindering drug development efforts. We previously identified high-throughput screening hits that bind to a site at the interface between the two variable domains of the LC homodimer. We hypothesized that extending the stabilizers beyond this initially characterized binding site would improve affinity. Here, using protease sensitivity assays, we identified stabilizers that can be divided into four substructures. Some stabilizers exhibit nanomolar EC50 values, a 3000-fold enhancement over the screening hits. Crystal structures reveal a key π-πstacking interaction with a conserved tyrosine residue that was not utilized by the screening hits. These data provide a foundation for developing LC stabilizers with improved binding selectivity and enhanced physicochemical properties.
- Yan, Nicholas L.,Santos-Martins, Diogo,Nair, Reji,Chu, Alan,Wilson, Ian A.,Johnson, Kristen A.,Forli, Stefano,Morgan, Gareth J.,Petrassi, H. Michael,Kelly, Jeffery W.
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p. 6273 - 6299
(2021/06/01)
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- CD16A BINDING AGENTS AND USES THEREOF
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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.
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Paragraph 00494; 00572; 00577; 00582; 00587; 00593; 00611
(2019/07/20)
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- Microwave-assisted synthesis of functionalized spirohydantoins as 3-D privileged fragments for scouting the chemical space
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Fragment-based drug design has been successfully applied to a large set of proteins, however in order to expand this concept to the most demanding targets, such as protein-protein interactions, it is required to enrich current fragment libraries with new and original 3D privileged fragments. Our goal was to develop a rapid microwave-assisted synthesis of 27 new privileged spirohydantoin fragments. Among them 24 compounds showed a high water solubility. These molecules were plotted according to the normalized principal moments of inertia of their minimized conformers, and most of the compounds were prone to occupy under-populated regions of the triangular plot. Finally we demonstrated that the hydantoin ring can be selectively N-monoalkylated providing the access to rapid functionalization for further elaboration.
- Prevet, Hugues,Flipo, Marion,Roussel, Pascal,Deprez, Benoit,Willand, Nicolas
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supporting information
p. 2888 - 2894
(2016/06/14)
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- Evaluation of spiropiperidine hydantoins as a novel class of antimalarial agents
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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.
- 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
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p. 5144 - 5150
(2015/03/30)
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- IMIDAZOAZEPINONE COMPOUNDS
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Compound of Formula (I) are described: Forumla (I) including pharmaceutically acceptable salts thereof, as well as pharmaceutical formulations or medicaments thereof and the use thereof in the treatment of disorders such as atherosclerosis, multiple scler
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Page/Page column 23-24
(2011/02/24)
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- A NEW PEPTIDE DEFORMYLASE INHIBITOR COMPOUND AND MANUFACTURING PROCESS THEREOF
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The present invention relates to the novel antibacterial compounds having potent antibacterial activity as inhibitors of peptide deformylase. This invention further relates to pharmaceutically acceptable salts thereof, to processes for their preparation, and to pharmaceutical compositions containing them as an active ingredient.
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Page/Page column 7
(2010/07/08)
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- SUBSTITUTED -1,3,8-TRIAZASPIRO[4.5]DECANE-2,4-DIONES
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The present invention relates to substituted 1,3,8-triazaspiro[4.5]decame-2,4-diones useful as HIF prolyl hydroxylase inhibitors to treat anemia and like conditions.
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Page/Page column 35
(2010/12/31)
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- METHOD OF MAKING IMIDAZOAZEPINONE COMPOUNDS
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A method of making a compound of Formula I: is carried out by (a) providing a compound of Formula (II) or (III): wherein ring A is C3-14 aryl or C3-14 heteroaryl such as phenyl or furanyl, and then (b) combining the compound of Formula (II) or (III) with an acid to produce a compound of Formula I.
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Page/Page column 38-39
(2009/07/03)
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- ENANTIOMERICALLY ENRICHED IMIDAZOAZEPINONE COMPOUNDS
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The present invention provides an enantiomerically pure compound of Formula (I) along with pharmaceutical formulations containing the same and methods of use thereof.
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Page/Page column 15
(2009/06/27)
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- A NEW PEPTIDE DEFORMYLASE INHIBITOR COMPOUND AND MANUFACTURING PROCESS THEREOF
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The present invention relates to the novel antibacterial compounds having potent antibacterial activity as inhibitors of peptide deformylase. This invention further relates to pharmaceutically acceptable salts thereof, to processes for their preparation, and to pharmaceutical compositions containing them as an active ingredient.
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Page/Page column 14
(2009/01/24)
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- IMIDAZOAZEPHINONE COMPOUNDS
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The invention relates to compounds of formula (I): along with pharmaceutical compositions containing the same and methods of use thereof.
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Page/Page column 17
(2008/06/13)
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- Hydantoin compounds
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The invention relates to the use of hydantoin compounds useful for treating or preventing autoimmune disorders. The present invention also provides compositions and uses thereof.
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Page/Page column 10
(2010/11/24)
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- HIV integrase inhibitors
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Compounds of the present disclosure are spirocycle-substituted pyrimidinecarboxamides. Also disclosed are pharmaceutical compositions comprising the compounds, and methods of using the compounds. The compounds are useful for treating HIV infection and AIDS.
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Page/Page column 19
(2010/02/14)
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- Parallel solution- and solid-phase synthesis of spirohydantoin derivatives as neurokinin-1 receptor ligands
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The combination of the 3,5-bis(trifluoromethyl)phenyl group with a spirohydantoin motive as a central scaffold was the basis for the design of a combinatorial library targeted towards the neurokinin-1 receptor. A solution- and solid-phase procedure is described and binding affinities of representative compounds presented.
- Bleicher, Konrad H.,Wuethrich, Yves,De Boni, Maxime,Kolczewski, Sabine,Hoffmann, Torsten,Sleight, Andrew J.
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p. 2519 - 2522
(2007/10/03)
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- Inhibitors or bone reabsorption and antagonists of vitronectin receptors
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Novel inhibitors of bone reabsorption and antagonists of vitronectin receptors The present invention relates to 5-membered ring heterocycles of the formula I, in which E, F, G, W, Y and Z have the meaning given in the patent claims, to their preparation a
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- Some benzenesulfonamido-substituted valerophenones that are selective antagonists for the 5-HT(2C) receptor
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Substituted benzenesulfonyl derivatives of m-aminovalerophenones bearing a 1,3,8-triazaspiro[4.5]decane-2,4-dione at the alkyl terminus are the first known, selective ligands for the 5-HT(2C) receptor. A brief structure-activity relationship of this series is outlined.
- Weinhardt, Klaus K.,Bonhaus, Douglas W.,De Souza, Andrea
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p. 2687 - 2692
(2007/10/03)
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