- A reassessment of mycophenolic acid as a lead compound for the development of inhibitors of chikungunya virus replication
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Mycophenolic acid (MPA) has been previously reported as an inhibitor of the chikugunya virus (CHIKV) with an EC50 value of 0.2 μM. We used MPA as a lead compound designing and synthesizing a series of isatins and benzolactones in a typical medicinal chemistry program. The synthesis and testing of 19 derivatives produced compounds with no desired activity which prompted us to retest the lead compound, MPA. We can reveal that MPA shows no anti-CHIKV activity and therefore needs to be reassessed as a lead compound for this target.
- Rashad, Adel A.,Neyts, Johan,Leyssen, Pieter,Keller, Paul A.
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p. 1294 - 1306
(2018/03/08)
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- COMPOUNDS, COMPOSITIONS, AND METHODS FOR MODULATING CFTR
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The present disclosure is directed to disclosed compounds that modulate, e.g., address underlying defects in cellular processing of CFTR activity.
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Paragraph 0153
(2017/08/01)
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- QUINAZOLINES AND AZAQUINAZOLINES AS DUAL INHIBITORS OF RAS/RAF/MEK/ERK AND PI3K/AKT/PTEN/MTOR PATHWAYS
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The present application provides novel quinazolines and azaquinazolines and pharmaceutically acceptable salts thereof. Also provided are methods for preparing these compounds. These compounds are useful in for co-regulating RAS/RAF/MEK/ERK and PI3K/AKT/PTEN/mTOR pathways by administering a therapeutically effective amount of one or more of the compounds of formula (I), wherein X, Y, T and R4, and R6 to R8' are defined herein, to a patient. By doing so, these compounds are effective in treating conditions associated with the dysregulation of the RAS/RAF/MEK/ERK and PI3K/AKT/PTEN/mTOR pathways. A variety of conditions can be treated using these compounds and include diseases which are characterized by abnormal cellular proliferation. In one embodiment/ the disease is cancer.
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Page/Page column 81
(2014/10/29)
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- A palladium-catalyzed synthesis of isatins (1H-Indole-2,3-diones) from 1-(2-haloethynyl)-2-nitrobenzenes
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An inherently regiospecific synthesis of isatins (1H-indole-2,3-diones) starting from 1-halo-2-nitrobenzenes is described. The isatins are formed by an intramolecular palladium-catalyzed annulation of 2-(2-haloethynyl)-1-nitrobenzenes via the formation of 2-haloisatogens.
- S?derberg, Bj?rn C.G.,Gorugantula, Sobha P.,Howerton, Chet R.,Petersen, Jeffrey L.,Dantale, Shubhada W.
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experimental part
p. 7357 - 7363
(2009/12/04)
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- Synthesis and biological evaluation of quinoline salicylic acids as P-selectin antagonists
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Leukocyte recruitment of sites of inflammation and tissue injury involves leukocyte rolling along the endothelial wall, followed by firm adherence of the leukocyte, and finally transmigration of the leukocyte across cell junctions into the underlying tissue. The initial rolling step is mediated by the interaction of leukocyte glycoproteins containing active moieties such as sialyl Lewisx (sLex) with P-selectin expressed on endothelial cells. Consequently, inhibition of this interaction by means of a small molecule P-selectin antagonist is an attractive strategy for the treatment of inflammatory diseases such as arthritis. High-throughput screening of the Wyeth chemical library identified the quinoline salicylic acid class of compounds (1) as antagonists of P-selectin, with potency in in vitro and cell-based assays far superior to that of sLex. Through iterative medicinal chemistry, we identified analogues with improved P-selectin activity, decreased inhibition of dihydrooratate dehydrogenase, and acceptable CYP profiles. Lead compound 36 was efficacious in the rat AIA model of rheumatoid arthritis.
- Kaila, Neelu,Janz, Kristin,DeBernardo, Silvano,Bedard, Patricia W.,Camphausen, Raymond T.,Tam, Steve,Tsao, Desirée H.H.,Keith Jr., James C.,Nickerson-Nutter, Cheryl,Shilling, Adam,Young-Sciame, Ruth,Wang, Qin
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- The synthesis and resolution of 2,2′-, 4,4′-, and 6,6′-substituted chiral biphenyl derivatives for application in the preparation of chiral materials
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Various routes were examined for the synthesis of chiral biphenyl species that are substituted at the 2,2′, 4,4′ and 6,6′ positions. Because the biaryl bond is tetrasubstituted, many coupling reactions were not suitable. The most reliable coupling reaction proved to be the Ullmann, which gave the desired product in 82% yield. The products were required as the starting point for the preparation of chiral materials using these as the monomer. For this reason, a route was required that produced large quantities of both enantiomers. The two enantiomers were resolved at the penultimate step by the use of chiral HPLC. A complicating feature proved to be the necessity to have a reactive group at the 4,4′ positions, which would permit polymerization though this point. Ultimately, we employed an Ullmann coupling on a dibrominated arene, which occurred selectively at the more hindered bromine by virtue of the directing effect of an ortho ester substituent.
- Montoya-Pelaez, Pedro J.,Uh, Yoon-Seo,Lata, Christopher,Thompson, Matthew P.,Lemieux, Robert P.,Crudden, Cathleen M.
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p. 5921 - 5929
(2007/10/03)
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