- Total synthesis of trans, trans- Sanguinamide B and conformational isomers
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The first total synthesis of Sanguinamide B is reported, prepared via an efficient synthetic strategy. The natural product, trans,trans-Sanguinamide B (1), was generated in a thermodynamic ratio with trans,cis-Sanguinamide B (2) and cis,cis-Sanguinamide B
- Singh, Erinprit K.,Ramsey, Deborah M.,McAlpine, Shelli R.
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- Highly efficient, multigram and enantiopure synthesis of (S)-2-(2,4′-bithiazol-2-yl)pyrrolidine
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(S)-2-(4-Bromo-2,4′-bithiazole)-1-(tert-butoxycarbonyl)pyrrolidine ((S)-1) was obtained as a single enantiomer and in high yield by means of a two-step modified Hantzsch thiazole synthesis reaction when bromoketone 3 and thioamide (S)-4 were used. Further conversion of (S)-1 into trimethyltin derivative (S)-2 broadens the scope for further cross-coupling reactions.
- Just-Baringo, Xavier,Bruno, Paolo,Albericio, Fernando,álvarez, Mercedes
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- A Potent, Selective, and Orally Bioavailable HCV NS5A Inhibitor for Treatment of Hepatitis C Virus: (S)-1-((R)-2-(Cyclopropanecarboxamido)-2-phenylacetyl)-N-(4-phenylthiazol-2-yl)pyrrolidine-2-carboxamide
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Starting from the initial lead 4-phenylthiazole 18, a modest HCV inhibitor (EC50 = 9440 nM), a series of structurally related thiazole derivatives has been identified as a novel chemical class of potent and selective HCV NS5A inhibitors. The introduction of a carboxamide group between the thiazole and pyrrolidine ring (42) of compound 18 resulted in a dramatic increase in activity (EC50 = 0.92 nM). However, 42 showed only moderate pharmacokinetic properties and limited oral bioavalability of 18.7% in rats. Further optimization of the substituents at the 4-position of the thiazole ring and pyrrolidine nitrogen of the lead compound 42 led to the identification of compound 57, a highly potent and selective NS5A inhibitor of HCV (EC50 = 4.6 nM), with greater therapeutic index (CC50/EC50 > 10000). Pharmacokinetic studies revealed that compound 57 had a superior oral exposure and desired bioavailability of 45% after oral administration in rats.
- Kang, Iou-Jiun,Hsu, Sheng-Ju,Yang, Hui-Yun,Yeh, Teng-Kuang,Lee, Chung-Chi,Lee, Yen-Chun,Tian, Ya-Wen,Song, Jen-Shin,Hsu, Tsu-An,Chao, Yu-Sheng,Yueh, Andrew,Chern, Jyh-Haur
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- Synthetic Studies on Alotamide A: Construction of N-Demethylalotamide A
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Several approaches to the synthesis of cyclodepsipeptide natural product alotamide A are described, eventually affording a very advanced N-demethylated analogue of the targeted natural product. The difficulties found in our endeavors on the synthesis of alotamide A have allowed us to gather some valuable information regarding the most convenient synthetic step for each key transformation. The intramolecular Csp2?Csp2 Stille cross-coupling and the macrolactam formation were found to be reliable protocols for the final construction of the alotamide A skeleton.
- Domínguez, Marta,Román, David,Souto, José A.,de Lera, ángel R.
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p. 6057 - 6070
(2021/12/10)
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- HMG-COA REDUCTASE DEGRADATION INDUCING COMPOUND
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The present invention relates HMG-CoA reductase degradation inducing compounds. Specifically, the present invention relates a bifunctional compound in which a HMG-CoA reductase binding moiety and an E3 ubiquitin ligase-binding moiety are linked by a chemical linker. The present invention also relates a method for preparing the compounds, and a method for degradation of HMG-CoA reducatase using the compounds, as well as use for prevention or treatment of HMG-CoA reductase related diseases using the compounds.
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Paragraph 661-664
(2021/10/11)
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- MDM2 DEGRADERS AND USES THEREOF
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The present invention relates to compounds and methods useful for the modulation of mouse double minute 2 homolog ("MDM2") protein via ubiquitination and/or degradation by compounds according to the present invention.
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Paragraph 001326; 001327-001328
(2021/09/26)
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- BIFUNCTIONAL COMPOUNDS FOR DEGRADING BTK VIA UBIQUITIN PROTEOSOME PATHWAY
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The present invention relates to compounds of formula (I) useful for degrading BTK via a ubiquitin proteolytic pathway. The invention also provides pharmaceutically acceptable compositions comprising said compounds and methods of using the compositions in the treatment of various disease, conditions, or disorders.
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Paragraph 0461-0462
(2021/05/15)
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- IRAK DEGRADERS AND USES THEREOF
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The present invention provides compounds, compositions thereof, and methods of using the same. The compounds include an IRAK binding moiety capable of binding to IRAK4 and a degradation inducing moiety (DIM). The DIM could be DTM a ligase binding moiety (LBM) or lysine mimetic. The compounds could be useful as IRAK protein kinase inhibitors and applied to IRAK mediated disorders.
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Paragraph 00920; 002242-002244
(2021/01/23)
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- (S)-4/5-phenyl-2-(pyrrolidin-2-yl)thiazole TRPV1 antagonists as well as preparation and application thereof
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The invention discloses (S)-4/5-phenyl-2-(pyrrolidin-2-yl)thiazole novel TRPV1 antagonists as well as a preparation method and application thereof, and particularly relates to compounds represented bya general formula (I) or a general formula (II) and a pharmaceutically acceptable salt thereof. The compound have a strong analgesic effect, the activity of part of the compounds is far higher than that of a TRPV1 receptor antagonist BCTC, almost no body temperature rise side effect exists, and the invention further relates to a preparation method of the compounds and pharmaceutical preparationscontaining the compounds.
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- IRAK DEGRADERS AND USES THEREOF
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The present invention provides compounds, compositions thereof, and methods of using the same.
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Paragraph 00962; 001086-001088
(2020/06/19)
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- BIFUNCTIONAL COMPOUNDS FOR DEGRADING BTK VIA UBIQUITIN PROTEOSOME PATHWAY
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The present invention relates to compounds useful for degrading BTK via a ubiquitin proteolytic pathway. The invention also provides pharmaceutically acceptable compositions comprising said compounds and methods of using the compositions in the treatment of various disease, conditions, or disorders.
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Paragraph 0932; 0933; 0934
(2020/05/21)
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- IRAK DEGRADERS AND USES THEREOF
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The present invention provides compounds, compositions thereof, and methods of using the same.
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Paragraph 3592; 3593
(2019/07/10)
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- MODULATORS OF PROTEOLYSIS AND ASSOCIATED METHODS OF USE
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The present disclosure relates to bifunctional compounds, which find utility as modulators of Kirsten rat sarcoma protein (target protein). In particular, the present disclosure is directed to bifunctional compounds, which contain on one end a Von Hippel-Lindau, cereblon, Inhibitors of Apotosis Proteins or mouse double-minute homolog 2 ligand which binds to the respective E3 ubiquitin ligase and on the other end a moiety which binds the target protein, such that the target protein is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of target protein. The present disclosure exhibits a broad range of pharmacological activities associated with degradation/inhibition of target protein. Diseases or disorders that result from aggregation, accumulation, and/or overactivation of the target protein are treated or prevented with compounds and compositions of the present disclosure.
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- ALANINE-BASED MODULATORS OF PROTEOLYSIS AND ASSOCIATED METHODS OF USE
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The description relates to inhibitors of Apoptosis Proteins (TAPs) binding compounds, including Afunctional compounds comprising the same, which find utility as modulators of targeted ubiquitination, especially inhibitors of a variety of polypeptides and other proteins which are degraded and/or otherwise inhibited by bifunctional compounds according to the present invention. In particular, the description provides compounds, which contain on one end a ligand which binds to the IAP E3 ubiquitin ligase and on the other end a moiety which binds a target protein such that the target protein is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of that protein. Compounds can be synthesized that exhibit a broad range of pharmacological activities consistent with the degradation/inhibition of targeted polypeptides of nearly any type.
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Paragraph 00369
(2017/02/09)
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- PROLINE DERIVATIVES
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Compounds of formula (I): wherein A, B, C, D, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, m, n, p, q, r, t, u, and v are defined herein. Also disclosed is a method for treating hepatitis C virus infection with these compounds.
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- Organic Compounds
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The present invention is directed to a compound of the formula: or pharmaceutically acceptable salts thereof and use of such compounds for treating proliferative diseases such as cancer, in mammals.
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Page/Page column 12
(2011/04/18)
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- Antagonists of inhibitor of apoptosis proteins based on thiazole amide isosteres
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A series of IAP antagonists based on thiazole or benzothiazole amide isosteres was designed and synthesized. These compounds were tested for binding to the XIAP-BIR3 and ML-IAP BIR using a fluorescence polarization assay. The most potent of these compound
- Cohen, Frederick,Koehler, Michael F.T.,Bergeron, Philippe,Elliott, Linda O.,Flygare, John A.,Franklin, Matthew C.,Gazzard, Lewis,Keteltas, Stephen F.,Lau, Kevin,Ly, Cuong Q.,Tsui, Vickie,Fairbrother, Wayne J.
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scheme or table
p. 2229 - 2233
(2010/06/15)
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- PDF INHIBITORS
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The invention relates to novel compounds that are inhibitors of peptidyl deformylase (PDF). The compounds are useful as antimicrobials and antibiotics. The compounds of the invention display selective inhibition of peptidyl deformylase versus other metalloproteinases such as MMPs. Methods of preparation and uses of the compounds are also disclosed.
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Page/Page column 35
(2010/11/28)
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- Kinetic control of proline amide rotamers: Total synthesis of trans,trans- and cis,cis-ceratospongamide
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Ceratospongamide is a cyclic peptide natural product that is biosynthesized as a mixture of two proline rotamers. Remarkably, these rotamers do not detectably interconvert at temperatures up to 100 °C. Here we report high-yielding syntheses of each rotame
- Deng, Shaojiang,Taunton, Jack
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p. 916 - 917
(2007/10/03)
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- SYNTHESIS OF A TRH ANALOG WITH A C-TERMINAL THIOAMIDE GROUP
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The synthesis of a new TRH analog containing a C-terminal thioamide group, L-pyroglutamyl-L-histydyl-L-proline thioamide has been described.The peptide has been shown to exhibit TRH receptor-binding affinity, as well as the TSH- and α-MSH-releasing activities matching those of the natural TRH.
- Kruszynski, Marian
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