- Influence of Linker Attachment Points on the Stability and Neosubstrate Degradation of Cereblon Ligands
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Proteolysis targeting chimeras (PROTACs) hijacking the cereblon (CRBN) E3 ubiquitin ligase have emerged as a novel paradigm in drug development. Herein we found that linker attachment points of CRBN ligands highly affect their aqueous stability and neosubstrate degradation features. This work provides a blueprint for the assembly of future heterodimeric CRBN-based degraders with tailored properties.
- Bricelj, Ale?a,Dora Ng, Yuen Lam,Ferber, Dominic,Gütschow, Michael,Kr?nke, Jan,Kuchta, Robert,Müller, Sina,Monschke, Marius,Sosi?, Izidor,Steinebach, Christian,Wagner, Karl G.
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supporting information
p. 1733 - 1738
(2021/11/16)
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- A kind of diaryl hydanto?n derivatives, its preparation method, pharmaceutical composition and application
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Provided are a compound as represented by formula I, or pharmaceutically acceptable salt, solvate, precursor drug, stereoisomer, tautomer, polymorph or metabolite thereof, pharmaceutical composition containing same, and uses thereof in the preparation of drugs for treating androgen receptor related diseases.
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Paragraph 0117
(2016/10/20)
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- MONOCARBOXYLATE TRANSPORT MODULATORS AND USES THEREOF
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The invention generally relates to the field of monocarboxylate transport modulators, e.g., monocarboxylate transport inhibitors, and more particularly to new substituted-quinolone compounds, the synthesis and use of these compounds and their pharmaceutical compositions, e.g., in treating, modulating, forestalling and/or reducing physiological conditions associated with monocarboxylate transport activity such as in treating cancer and other neoplastic disorders, inflammatory diseases, disorders of abnormal tissue growth and fibrosis including cardiomyopathy, obesity, diabetes, cardiovascular diseases, tissue and organ transplant rejection, and malaria.
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Paragraph 00117
(2016/06/20)
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- HETEROARYL COMPOUNDS AND USES THEREOF
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The present invention provides compounds, pharmaceutically acceptable compositions thereof, and methods of using the same. It has now been found that compounds of this invention, and pharmaceutically acceptable compositions thereof, are effective as inhibitors of one or more protein kinases. Such compounds have general formula I or a pharmaceutically acceptable salt thereof, wherein Ring A, Ring B, W, Ry, R3 and R4 are as defined herein.
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Paragraph 00866
(2016/06/28)
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- Method for synthesizing 2-azidomethyl-4-nitrobenzoyl chloride
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The invention provides a synthetic route for a novel protective group, namely 2-azidomethyl-4-nitrobenzoyl chloride. 2-methyl-4-nitrobenzoic acid is used as a raw material, and the 2-azidomethyl-4-nitrobenzoyl chloride is synthesized through the five step
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Paragraph 0011
(2017/01/23)
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- BIOREVERSABLE PROMOIETIES FOR NITROGEN-CONTAINING AND HYDROXYL-CONTAINING DRUGS
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Disclosed are promoieties of the following formula which can be used to form prodrugs of nitrogen-containing or hydroxyl-containing drug or a pharmaceutically active agent: (I) and pharmaceutical compositions comprising the prodrugs.
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Page/Page column 138
(2015/06/18)
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- Pyrrole inhibitors of S-nitrosoglutathione reductase as therapeutic agents
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The present invention is directed to inhibitors of S-nitrosoglutathione reductase (GSNOR), pharmaceutical compositions comprising such GSNOR inhibitors, and methods of making and using the same.
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Page/Page column 286
(2015/11/16)
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- MACROCYCLIC FACTOR VIIA INHIBITORS
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The present invention provides compounds of Formula (I) as defined in the specification and compositions comprising any of such novel compounds. These compounds are Factor VIIa inhibitors which may be used as medicaments.
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- MACROCYCLIC FACTOR VIIA INHIBITORS
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The present invention provides compounds of Formula (I): as defined in the specification and compositions comprising any of such novel compounds. These compounds are Factor VIIa inhibitors which may be used as medicaments.
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- DIBENZOCYCLOHEPTATONE DERIVATIVES AND PHARMACEUTICAL AGENTS CONTAINING SAID COMPOUNDS
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The present invention relates to compounds of the formula I wherein R1, R2, R3, R4, X and Y have the meanings given in the description. The compounds have an action which is immunomodulating and inhibits or regulates the release of IL-1β and/or TNF-α. The
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Page/Page column 34-35
(2012/05/20)
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- Design, synthesis, biological evaluation and X-ray crystal structure of novel classical 6,5,6-tricyclic benzo[4,5]thieno[2,3-d]pyrimidines as dual thymidylate synthase and dihydrofolate reductase inhibitors
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Classical antifolates (4-7) with a tricyclic benzo[4,5]thieno[2,3-d] pyrimidine scaffold and a flexible and rigid benzoylglutamate were synthesized as dual thymidylate synthase (TS) and dihydrofolate reductase (DHFR) inhibitors. Oxidative aromatization of
- Zhang, Xin,Zhou, Xilin,Kisliuk, Roy L.,Piraino, Jennifer,Cody, Vivian,Gangjee, Aleem
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experimental part
p. 3585 - 3594
(2011/07/08)
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- SUBSTITUTED CYCLOPROPYL COMPOUNDS, COMPOSITIONS CONTAINING SUCH COMPOUNDS AND METHODS OF TREATMENT
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Substituted cyclopropyl compounds of the formula I: are disclosed as useful for treating or preventing type 2 diabetes and similar conditions. Pharmaceutically acceptable salts are included as well. The compounds are useful as agonists of the g-protein coupled receptor GPR-119.
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Page/Page column 127
(2011/02/24)
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- [1, 2, 4] TRIAZOLO [1, 5-A] PYRIDINES AS JAK INHIBITORS
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Novel [1,2,4]triazolo[1,5-a]pyridine compounds are disclosed that have a Formula represented by the following: (I). The compounds may be prepared as pharmaceutical compositions, and may be used for the prevention and treatment of a variety of conditions in mammals including humans, including by way of non-limiting example, joint disease, inflammation, and others.
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Page/Page column 59
(2010/04/03)
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- COMPOUNDS
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A compound of formula (I): or its salts or pharmaceutically acceptable derivatives thereof wherein; A represents a chemical moiety with the general formula (II): X is selected from a group consisting of CH2, C(=O), CH(R5), C(R5)(R6) or C(R5)(R6)CH2; R1 is selected from the group consisting of optionally substituted arylalkyl, and optionally substituted heteroarylalkyl; R2 is selected from the group consisting of optionally substituted aryl or optionally substituted heteroaryl or NR7R8; R3 is selected from the group consisting of hydrogen, halogen, hydroxyl, alkoxy, aryloxy, optionally substituted alkyl, optionally substituted amino, optionally substituted amino sulfonyl or nitrile; R4 is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted acyl, optionally substituted sulfonyl, optionally substituted sulfamoyl, optionally substituted aryl, optionally substituted arylalkyl, and optionally substituted heteroaryl; R5 and R6 for each occurrence is optionally substituted alkyl; R7 and R8 are the same or different and each represents hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted arylalkyl, optionally substituted aryl or optionally substituted heteroaryl; n = 1 or 2 is provided. Pharmaceutical compositions comprising the compounds are also provided. The compounds are useful in treating various conditions including arrhythmia.
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Page/Page column 31-32
(2010/12/29)
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- 4-PHENOXY-6-ARYL-1H-PYRAZOLO[3,4-D]PYRIMIDINE AND N-ARYL-6-ARYL-1H-PYRAZOLO[3,4-D]PYRIMIDIN-4-AMINE COMPOUNDS, THEIR USE AS MTOR KINASE AND PI3 KINASE INHIBITORS, AND THEIR SYNTHESES
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The invention relates to 4,6-disubstituted-1H-pyrazolo[3,4-d]pyrimidin-4-amine compounds, including 4-phenoxy-6-aryl-1H-pyrazolo[3,4-d]pyrimidine and N-aryl-6-aryl-1H-pyrazolo[3,4-d]pyrimidin-4-amine compounds of the Formula I: or a pharmaceutically accep
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Page/Page column 26
(2010/02/17)
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- PYRIMIDINE DERIVATIVES CAPABLE OF INHIBITING ONE OR MORE KINASES
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A first aspect of the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt or ester thereof, formula (I): wherein: R1 is C3-8-cycloalkyl; X is O, NR7 or C3-6-heterocycloalkyl; R2 is aryl, heteroaryl, fused or unfused aryl-C3-6-heterocycloalkyl or fused or unfused heteroaryl-C3-6-heterocycIoalkyl, each of which is optionally substituted by one or more substitutents selected from aryl, heteroaryl, C1-6-alkyl, C3-7-cycloalkyl and a group A, wherein said C1-6-alkyl group is optionally substituted by one or more substituents selected from aryl, heteroaryl, R10 and a group A, said heteroaryl group is optionally substituted by one or more R10 groups; and wherein said C3-6-heterocycloalkyl group optionally contains one or more groups selected from oxygen, sulfur, nitrogen and CO; R3 is C1-6-alkyl optionally substituted by one or more substituents selected from aryl, heteroaryl, -NR4R5, -OR6, -NR7(CO)R6, -NR7(CO)NR4R5, -NR7SO2R6, -NR7COOR7, -CONR4R5, C3-6-heterocycloalkyl and formula (a, b, c): wherein R4-7 and A are as defined in the claims. Further aspects relate to the use of said compounds in the treatment of various therapeutic disorders, and more particularly as inhibitors of one or more kinases.
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Page/Page column 101
(2009/10/30)
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- INDOLE DERIVATIVES USEFUL AS PPAR ACTIVATORS
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There is provided according to the invention novel compounds of Formula (I) or pharmaceutically acceptable salts or solvates thereof: (I) useful as PPAR activators.
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Page/Page column 28
(2009/05/30)
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- Rational design of the first small-molecule antagonists of NHERF1/EBP50 PDZ domains
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This report describes the first small-molecule antagonists that specifically target the ligand-binding pocket of PDZ domains of NHERF1 multi-functional adaptor protein. Comparison of the peptide sequence homology between the native ligand of NHERF1 PDZ do
- Mayasundari, Anand,Ferreira, Antonio M.,He, Liwen,Mahindroo, Neeraj,Bashford, Don,Fujii, Naoaki
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p. 942 - 945
(2008/09/18)
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- Indole-2-amide based biochemical antagonist of Dishevelled PDZ domain interaction down-regulates Dishevelled-driven Tcf transcriptional activity
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We designed and synthesized a series of indole-2-amide-based compounds that antagonize interaction between the Dishevelled (Dvl) PDZ domain and a peptide derived from the natural PDZ ligand Frizzled-7 (Fz7). These compounds inhibit Tcf-mediated transcript
- Mahindroo, Neeraj,Punchihewa, Chandanamali,Bail, Allison M.,Fujii, Naoaki
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p. 946 - 949
(2008/09/20)
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- Design, synthesis, and evaluation of cyclic amide/imide-bearing hydroxamic acid derivatives as class-selective histone deacetylase (HDAC) inhibitors
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A series of hydroxamic acid derivatives bearing a cyclic amide/imide group as a linker and/or cap structure, prepared during our structural development studies based on thalidomide, showed class-selective potent histone deacetylase (HDAC)-inhibitory activity. Structure-activity relationship studies indicated that the steric character of the substituent introduced at the cyclic amide/imide nitrogen atom, the presence of the amide/imide carbonyl group, the hydroxamic acid structure, the shape of the linking group, and the distance between the zinc-binding hydroxamic acid group and the cap structure are all important for HDAC-inhibitory activity and class selectivity. A representative compound (30w) showed potent p21 promoter activity, comparable with that of trichostatin A (TSA), and its cytostatic activity against cells of the human prostate cell line LNCaP was more potent than that of the well-known HDAC inhibitor, suberoylanilide hydroxamic acid (SAHA).
- Shinji, Chihiro,Maeda, Satoko,Imai, Keisuke,Yoshida, Minoru,Hashimoto, Yuichi,Miyachi, Hiroyuki
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p. 7625 - 7651
(2007/10/03)
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- ARYL-AMINO SUBSTITUTED PYRROLOPYRIMIDINE MULTI-KINASE INHIBITING COMPOUNDS
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Compounds represented by Formula (I): or stereoisomers or pharmaceutically acceptable salts thereof, are inhibitors of least two of the Abl, Aurora-A, Blk, c-Raf, cSRC, Src, PRK2, FGFR3, Flt3, Lck, Mekl, PDK-1, GSK3?, EGFR, p70S6K, BMX, SGK, CaMKII, Tie-2
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Page/Page column 155-156
(2008/06/13)
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- SMALL MOLECULE INHIBITION OF A PDZ-DOMAIN INTERACTION
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Novel compounds that have been found effective in inhibiting PDZ domain interactions, and particularly interactions of PDZ domains in MAGIs with the oncogenic (tumor suppressor) protein PTEN and interactions between the PDZ domain in the Dishevelled (Dvl)
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Page/Page column 24
(2008/06/13)
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- VIRAL POLYMERASE INHIBITORS
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An enantiomer, diastereoisomer or tautomer of a compound, represented by formula (I): wherein either A or B is nitrogen and the other B or A is C, and the radicals R1, R2, R3, R4, R5, R6, R7, R8, R9, and R10 are as defined herein, or a salt or ester thereof as viral polymerase inhibitors. The compound is used as an inhibitor of RNA dependent RNA polymerases, particularly those viral polymerases within the Flaviviridae family, more particularly to HCV polymerase.
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Page/Page column 63
(2008/06/13)
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- 5-Deazafolate analogues with a rotationally restricted glutamate or ornithine side chain: Synthesis and binding interaction with folylpolyglutamate synthetase
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Rotationally restricted analogues of 5-deazapteroyl-L-glutamate and (6R,6S)-5-deaza-5,6,7,8-tetrahydropteroyl-L-glutamate with a one-carbon bridge between the amide nitrogen and the 6'-position of the p-aminobenzoyl moiety were synthesized and tested as substrates for folylpolyglutamate synthetase (FPGS), a key enzyme in folate metabolism and an important determinant of the therapeutic potency and selectivity of classical antifolates. The corresponding bridged analogues of 5-deazapteroyl-L- ornithine and (6R,6S)-5-deaza-5,6,7,8-tetrahydropteroyl-L-ornithine were also synthesized as potential inhibitors. Condensation of diethyl L-glutamate with methyl 2-bromomethyl-4-nitrobenzoate followed by catalytic reduction of the nitro group, reductive coupling with 2-acetamido-6-formylpyrido[2,3- d]pyrimidin-4(3H)-one in the presence of dimethylaminoborane, and acidolysis with HBr/AcOH yielded 2-L-[5-[N-(2-acetamido-4(3H)-oxopyrido[2,3-d]pyrimidin- 6-yl)methylamino]-2,3-dihydro-1-oxo-2(1H)-isoindolyl]glutaric acid (1). When acidolysis was preceded by catalytic hydrogenation, the final product was the corresponding (6R,6S)-tetrahydro derivative 2. A similar sequence starting from methyl N(δ)benzyloxycarbonyl-L-ornithine led to 2-L-[5-[N-(2-amino- 4(3H)-oxopyrido[2,3-d]pyrimidin-6-yl)methylamino]-2,3-dihydro-1-oxo-2(1H)- isoindolyl]-5-aminopentanoic acid (3) and the (6R,6S)tetrahydro derivative 4. Compounds 3 and 4 were powerful inhibitors of recombinant human FPGS, whereas 1 and 2 were exceptionally efficient FPGS substrates, with the reduced compound 2 giving a Km (0.018 μM) lower than that of any other substrate identified to date. (6R,6S)-5-Deazatetrahydrofolate, in which the side chain is free to rotate, was rapidly converted to long-chain polyglutamates. In contrast, the reaction of 1 and 2 was limited to the addition of a single molecule of glutamic a cid. Hence rotational restriction of the side chain did not interfere with the initial FPGS-catalyzed reaction and indeed seemed to facilitate it, but the ensuing γ-glutamyl adduct was no longer an efficient substrate for the enzyme.
- Rosowsky, Andre,Forsch, Ronald A.,Null, Allison,Moran, Richard G.
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p. 3510 - 3519
(2007/10/03)
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- Regioselectivity of the Base-Induced Ring Cleavage of 1-Oxygenated Derivatives of Cyclobutabenzene
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Oxy anions 3 generated from 1,2-dihydrocyclobutabenzen-1-ones 1 through addition of a charged nucleophile or from 1-hydroxy-1,2-dihydrocyclobutabenzenes 2 by deprotonation with base lead to stable products through distal and/or proximal cleavage of the strained four-membered ring via benzyl carbanion 4 and/or aryl carbanion 5. A systematic study of this process reveals the relative stability of the two isomeric carbanions 4 and 5 as a key factor in determining the course of the ring-cleavage reaction. While benzyl carbanions 4 can be trapped with carbon electrophiles, attempts at trapping aryl carbanions 5 with electrophiles other than H+ failed. In protic solvents, the magnesium salt of the tertiary alcohol 2 shows an increased rate of proximal cleavage as compared to its alkali salts. From this, we conclude that, in contrast to benzyl carbanions 4, free aryl carbanions 5 are of transient existence only. Proximal C,C-bond cleavage seems to occur either through protonation of 5 from a fast, reversible equilibrium 3?5 in which 3 strongly predominates, or in protic solvents possibly even through a rate-limiting protonation of 3 at the aromatic C-atom, bypassing free anion 5 altogether. Thus, additional factors other than just the relative stability of isomeric carbanions 4 and 5 are of importance in determining the regiochemistry of the base-induced C,C-bond cleavage in ketones 1 and in alcohols 2.
- Gokhale, Abha,Schiess, Peter
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p. 251 - 267
(2007/10/03)
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