- Discovery of MK-4688: An Efficient Inhibitor of the HDM2-p53 Protein-Protein Interaction
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Identification of low-dose, low-molecular-weight, drug-like inhibitors of protein-protein interactions (PPIs) is a challenging area of research. Despite the challenges, the therapeutic potential of PPI inhibition has driven significant efforts toward this goal. Adding to recent success in this area, we describe herein our efforts to optimize a novel purine carboxylic acid-derived inhibitor of the HDM2-p53 PPI into a series of low-projected dose inhibitors with overall favorable pharmacokinetic and physical properties. Ultimately, a strategy focused on leveraging known binding hot spots coupled with biostructural information to guide the design of conformationally constrained analogs and a focus on efficiency metrics led to the discovery of MK-4688 (compound 56), a highly potent, selective, and low-molecular-weight inhibitor suitable for clinical investigation.
- Altman, Michael D.,Bogen, Stephane,Cai, Mingmei,Cammarano, Carolyn,Chen, Dapeng,Christopher, Matthew,Cryan, John,Daublain, Pierre,Dussault, Isabelle,Fradera, Xavier,Geda, Prasanthi,Goldenblatt, Peter,Hill, Armetta D.,Kemper, Raymond A.,Kutilek, Victoria,Li, Chaomin,Machacek, Michelle R.,Marshall, C. Gary,Martinez, Michelle,McCoy, Mark,Nair, Latha,Pan, Weidong,Reutershan, Michael H.,Scapin, Giovanna,Shizuka, Manami,Spatz, Marianne L.,Steinhuebel, Dietrich,Sun, Binyuan,Thompson, Christopher F.,Trotter, B. Wesley,Voss, Matthew E.,Wang, Xiao,Yang, Liping,Yeh, Tammie C.
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p. 16213 - 16241
(2021/11/16)
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- Immunomodulator
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The invention discloses an immunomodulator, and particularly relates to a compound for inhibiting IL-17A and application of the compound serving as the immunomodulator in preparation of drugs. The invention discloses application of a compound shown in a formula I or a stereoisomer thereof in preparation of medicines for inhibiting IL-17A, and provides a new choice for clinically screening and/or preparing medicines for treating diseases related to IL-17A activity.
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Paragraph 0254-0258
(2021/05/22)
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- Immunomodulator
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The invention discloses an immunomodulator, and particularly relates to a compound for inhibiting IL-17A and application of the compound serving as the immunomodulator in preparation of drugs. The invention discloses application of a compound shown in a f
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Paragraph 0118-0120
(2021/05/22)
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- SPIROCYCLIC INDANE ANALOGUES AS IL-17 MODULATORS
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A series of substituted spirocyclic indane derivatives of Formula (I), and analogues thereof, being potent modulators of human IL-17 activity, are accordingly of benefit in the treatment and/or prevention of various human ailments, including inflammatory
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Page/Page column 65; 66
(2020/02/06)
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- FUNCTIONALISED AMINE DERIVATIVES AS IL-17 MODULATORS
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A series of functionalised amine derivatives of formula (I) as defined herein, being potent modulators of human IL-17 activity, are accordingly of benefit in the treatment and/or prevention of various human ailments, including inflammatory and autoimmune disorders.
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Page/Page column 68
(2020/07/07)
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- Hydrogenation of alkenes via cooperative hydrogen atom transfer
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Radical hydrogenation via hydrogen atom transfer (HAT) to alkenes is an increasingly important transformation for the formation of thermodynamic alkane isomers. Current single-catalyst methods require stoichiometric oxidant in addition to hydride (H-) source to function. Here we report a new approach to radical hydrogenation: cooperative hydrogen atom transfer (cHAT), where each hydrogen atom donated to the alkene arrives from a different catalyst. Further, these hydrogen atom (H?) equivalents are generated from complementary hydrogen atom precursors, with each alkane requiring one hydride (H-) and one proton (H+) equivalent and no added oxidants. Preliminary mechanistic study supports this reaction manifold and shows the intersection of metal-catalyzed HAT and thiol radical trapping HAT catalytic cycles to be essential for effective catalysis. Together, this unique catalyst system allows us to reduce a variety of unactivated alkene substrates to their respective alkanes in high yields and diastereoselectivities and introduces a new approach to radical hydrogenation.
- Kattamuri, Padmanabha V.,West, Julian G.
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supporting information
p. 19316 - 19326
(2020/11/13)
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- SPIROCYCLIC INDOLINES AS IL-17 MODULATORS
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A series of substituted spirocyclic 2-oxoindoline derivatives, and analogues thereof, being potent modulators of human IL-17 activity, are accordingly of benefit in the treatment and/or prevention of various human ailments, including inflammatory and autoimmune disorders.
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Page/Page column 94
(2019/01/07)
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- SUBSTITUTED PYRROLOPYRIMIDINES AS HDM2 INHIBITORS
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The present invention provides substituted pyrrolopyrimidines as described herein or a pharmaceutically acceptable salt or solvate thereof. The representative compounds are useful as inhibitors of the HDM2 protein. Also disclosed are pharmaceutical compos
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Page/Page column 98
(2014/07/08)
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- 2,6,7 SUBSTITUTED PURINES AS HDM2 INHIBITORS
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The present invention provides 2,6,7 substituted purines as described herein or a pharmaceutically acceptable salt thereof. The representative compounds are useful as inhibitors of the HDM2 protein. Also disclosed are pharmaceutical compositions comprising the above compounds and potential methods of treating cancer using the same.
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Page/Page column 58-59
(2014/08/20)
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- Bis(phosphine)cobalt dialkyl complexes for directed catalytic alkene hydrogenation
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Planar, low-spin cobalt(II) dialkyl complexes bearing bidentate phosphine ligands, (P - P)Co-(CH2SiMe3)2, are active for the hydrogenation of geminal and 1,2-disubstituted alkenes. Hydrogenation of more hindered internal and endocyclic trisubstituted alkenes was achieved through hydroxyl group activation, an approach that also enables directed hydrogenations to yield contrasteric isomers of cyclic alkanes.
- Friedfeld, Max R.,Margulieux, Grant W.,Schaefer, Brian A.,Chirik, Paul J.
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p. 13178 - 13181
(2015/03/30)
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- Simple, chemoselective hydrogenation with thermodynamic stereocontrol
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Few methods permit the hydrogenation of alkenes to a thermodynamically favored configuration when steric effects dictate the alternative trajectory of hydrogen delivery. Dissolving metal reduction achieves this control, but with extremely low functional group tolerance. Here we demonstrate a catalytic hydrogenation of alkenes that affords the thermodynamic alkane products with remarkably broad functional group compatibility and rapid reaction rates at standard temperature and pressure.
- Iwasaki, Kotaro,Wan, Kanny K.,Oppedisano, Alberto,Crossley, Steven W. M.,Shenvi, Ryan A.
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p. 1300 - 1303
(2014/02/14)
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- Substituted Imidazopyridines as HDM2 Inhibitors
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The present invention provides substituted imidazopyridines as described herein or a pharmaceutically acceptable salt or solvate thereof. The representative compounds are useful as inhibitors of the HDM2 protein. Also disclosed are pharmaceutical compositions comprising the above compounds and potential methods of treating cancer using the same.
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Paragraph 0710
(2014/07/08)
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- Stereoselective Metal Catalysed Hydroboration of 4-Substituted 1-Methylidenecyclohexanes
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Rhodium catalysed hydroboration of 4-substituted 1-methylidenecyclohexanes gives cis-hydroboration products with high stereoselectivity.The effects influencing the stereochemistry are discussed.
- Hou, Xue-Long,Xie, Quan-Cheng,Dai, Li-Xin
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p. 2665 - 2678
(2007/10/03)
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- Directing Effects in Homogeneous Hydrogenation with PF6
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The presence of a ligating group, e.g., OH, CO2Me, C=O, or OMe, on an olefinic substrate is shown to direct the attack of the hydrogenation catalyst PF6/H2/CH2Cl2 from the face of the molecule containing the directing group.Isomerization is a minor side reaction in the cases studied.The origin of this effect is discussed and a model intermediate isolated.
- Crabtree, Robert H.,Davis, Mark W.
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p. 2655 - 2661
(2007/10/02)
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- The Properties of Liquid Crystal Materials Incorporating the -CH2O- Inter-ring Linkage
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To establish more securely the influence of the -CH2O- inter-ring linkage upon the properties of mesogens of both high and low dielectric anisotropy, a range of ethers with the following general structure has been prepared and their properties examined. The thermal and electro-optic properties of the compounds are discussed, and comparisons made where possible with analogous materials incorporating the -CH2CH2- linkage.
- Carr, N.,Gray, G. W.
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- 1-(TRANS-4 prime -N-ALKYLCYCLOHEXYL)-2-(4 double prime -CYANOPHENYL)ETHANES - A NEW SERIES OF STABLE NEMATOGENS OF POSITIVE DIELECTRIC ANISOTROPY.
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The synthesis and some important properties of the 1-(trans-4 prime -n-alkylcyclohexyl)-2-(4 double prime -cyanophenyl)ethanes - where n-alkyl equals C//1 to C//7 - are described.
- Carr,Gray,McDonnell
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