- TEAD INHIBITORS 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 00465; 00790
(2020/12/11)
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- Synthetic Analogues of the Snail Toxin 6-Bromo-2-mercaptotryptamine Dimer (BrMT) Reveal That Lipid Bilayer Perturbation Does Not Underlie Its Modulation of Voltage-Gated Potassium Channels
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Drugs do not act solely by canonical ligand-receptor binding interactions. Amphiphilic drugs partition into membranes, thereby perturbing bulk lipid bilayer properties and possibly altering the function of membrane proteins. Distinguishing membrane perturbation from more direct protein-ligand interactions is an ongoing challenge in chemical biology. Herein, we present one strategy for doing so, using dimeric 6-bromo-2-mercaptotryptamine (BrMT) and synthetic analogues. BrMT is a chemically unstable marine snail toxin that has unique effects on voltage-gated K+ channel proteins, making it an attractive medicinal chemistry lead. BrMT is amphiphilic and perturbs lipid bilayers, raising the question of whether its action against K+ channels is merely a manifestation of membrane perturbation. To determine whether medicinal chemistry approaches to improve BrMT might be viable, we synthesized BrMT and 11 analogues and determined their activities in parallel assays measuring K+ channel activity and lipid bilayer properties. Structure-activity relationships were determined for modulation of the Kv1.4 channel, bilayer partitioning, and bilayer perturbation. Neither membrane partitioning nor bilayer perturbation correlates with K+ channel modulation. We conclude that BrMT's membrane interactions are not critical for its inhibition of Kv1.4 activation. Further, we found that alkyl or ether linkages can replace the chemically labile disulfide bond in the BrMT pharmacophore, and we identified additional regions of the scaffold that are amenable to chemical modification. Our work demonstrates a strategy for determining if drugs act by specific interactions or bilayer-dependent mechanisms, and chemically stable modulators of Kv1 channels are reported.
- Dockendorff, Chris,Gandhi, Disha M.,Kimball, Ian H.,Eum, Kenneth S.,Rusinova, Radda,Ingólfsson, Helgi I.,Kapoor, Ruchi,Peyear, Thasin,Dodge, Matthew W.,Martin, Stephen F.,Aldrich, Richard W.,Andersen, Olaf S.,Sack, Jon T.
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p. 2733 - 2743
(2018/05/23)
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- BENZODIAZEPINES AS BROMODOMAIN INHIBITORS
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The present invention provides novel benzodiazepine derivatives of Formula I or pharmaceutically acceptable derivatives, polymorphs, salts or prodrugs thereof. Said compounds have potential as bromodomain (BRD) inhibitors.
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Page/Page column 62; 72
(2017/02/28)
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- Palladium-Catalyzed Incorporation of Two C1 Building Blocks: The Reaction of Atmospheric CO2 and Isocyanides with 2-Iodoanilines Leading to the Synthesis of Quinazoline-2,4(1H,3H)-diones
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A Pd-catalyzed insertion and cycloaddition of CO2 and isocyanide into 2-iodoanilines under atmospheric pressure has been developed and affords quinazoline-2,4(1H,3H)-diones through the formation of new C-C, C-O, and C-N bonds under mild conditions. This reaction provides a new and practical method not only for the construction of quinazoline-2,4(1H,3H)-diones but also for the efficient utilization of carbon dioxide.
- Xu, Pei,Wang, Fei,Wei, Tian-Qi,Yin, Ling,Wang, Shun-Yi,Ji, Shun-Jun
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supporting information
p. 4484 - 4487
(2017/09/11)
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- Stereoselective synthesis of spirocyclic oxindoles based on a one-pot Ullmann coupling/Claisen rearrangement and its application to the synthesis of a hexahydropyrrolo[2,3-b]indole alkaloid
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An efficient and convenient approach to the synthesis of spirocyclic oxindoles from iodoindoles has been developed. The most striking feature of this approach is that the sequential intramolecular Ullmann coupling and Claisen rearrangement proceeds in a one-pot manner to afford 3-spiro-2-oxindoles in good yield with excellent diastereoselectivity. Application of this one-pot reaction to chiral non-racemic tertiary alcohol substrates resulted in complete chirality transfer to the spirocyclic quaternary carbon. Using this method, asymmetric total synthesis of (-)-debromoflustramine B was accomplished.
- Miyamoto, Hiroshi,Hirano, Tomohiro,Okawa, Yoichiro,Nakazaki, Atsuo,Kobayashi, Susumu
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p. 9481 - 9493
(2013/10/08)
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- HETERO-BICYCLIC DERIVATIVES AS HCV INHIBITORS
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Inhibitors of HCV replication of formula (I) including stereochemically isomeric forms, and salts, hydrates, solvates thereof, wherein R and R' have the meaning as defined herein. The present invention also relates to processes for preparing said compounds, pharmaceutical compositions containing them and their use, alone or in combination with other HCV inhibitors,in HCV therapy.
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Page/Page column 68
(2012/02/13)
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- ANALOGUES FOR THE TREATMENT OR PREVENTION OF FLAVIVIRUS INFECTIONS
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Compounds represented by formula (I) described herein or pharmaceutically acceptable salts thereof, wherein A, B, B', X, Y, R1, R2, R2', R3, R3', R4, R4', R5, R5
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Page/Page column 90
(2011/10/13)
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- Total synthesis of (-)-flustramine B via one-pot intramolecular ullmann coupling and claisen rearrangement
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Total synthesis of (-)-flustramine B was achieved via one-pot intramolecular Ullmann coupling and Claisen rearrangement. A striking feature of this method of synthesis is that the sequential intramolecular Ullmann coupling and Claisen rearrangement reactions proceeds with concomitant deprotection of the methoxymethyl (MOM) group to afford spirocyclic oxindole with perfect asymmetric transmission in good overall yield.
- Hirano, Tomohiro,Iwakiri, Kanako,Miyamoto, Hiroshi,Nakazaki, Atsuo,Kobayashi, Susumu
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experimental part
p. 805 - 820
(2009/12/01)
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- First synthesis of 3,6′- and 3,7′-biquinoline derivatives
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The preparation of new 3,6′- and 3,7′-biquinoline derivatives was achieved by microwave-assisted Suzuki cross-coupling between N-protected 6- or 7-bromoquinolin-2(lH)-ones and quino-lin-3-ylboronic acid. Moreover, a new synthesis of 7-bromoquino-lin-2(lH)-one leading solely to the 7-substituted isomer was carried out. Thieme Stuttgart.
- Broch, Sidonie,Anizon, Fabrice,Moreau, Pascale
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body text
p. 2039 - 2044
(2009/04/03)
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- Condensed Heteroaromatic Ring Systems. XII. Synthesis of Indole Derivatives from Ethyl 2-Bromocarbanilates
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The palladium-catalyzed reaction of ethyl 2-bromocarbanilate with trimethylsilylacetylene yielded ethyl 2-(trimethylsilylethynyl)carbanilate, which was treated with sodium ethoxide to give indole.The carbanilates having a methyl or a bromo substituent were similarly transformed to corresponding indole derivatives.Furthermore, pyrrolo- and Pyrrolopyridines were synthesized by this method.Keywords---palladium-catalyzed reaction; trimethylsilylacetylene; ethyl 2-halocarbanilate; ethyl 2-halopyridinecarbamate; ethyl 2-(trimethylsilylethynyl)carbanylate; ethyl o-(trimethylsilylethynyl)pyridinecarbamate;indole;pyrrolopyridine
- Sakamoto, Takao,Kondo, Yoshinori,Iwashita, Shigeki,Yamanaka, Hiroshi
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p. 1823 - 1828
(2007/10/02)
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