- PYRIDINONE DERIVATIVES AS SELECTIVE CYTOTOXIC AGENTS AGAINST HIV INFECTED CELLS
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The present disclosure is directed to pyridinone derivatives of Formula I and their use for selectively killing HIV infected GAG-POL expressing cells without concomitant cytotoxicity to HIV nave cells, and for the treatment of infection by HIV, or for the treatment, prophylaxis or delay in the onset or progression of AIDS or AIDS Related Complex (ARC).
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Page/Page column 52-53
(2020/12/07)
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- Development of inhibitors against mycobacterium abscessus tRNA (m1G37) Methyltransferase (TrmD) Using Fragment-Based Approaches
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Mycobacterium abscessus (Mab) is a rapidly growing species of multidrug-resistant nontuberculous mycobacteria that has emerged as a growing threat to individuals with cystic fibrosis and other pre-existing chronic lung diseases. Mab pulmonary infections are difficult, or sometimes impossible, to treat and result in accelerated lung function decline and premature death. There is therefore an urgent need to develop novel antibiotics with improved efficacy. tRNA (m1G37) methyltransferase (TrmD) is a promising target for novel antibiotics. It is essential in Mab and other mycobacteria, improving reading frame maintenance on the ribosome to prevent frameshift errors. In this work, a fragment-based approach was employed with the merging of two fragments bound to the active site, followed by structure-guided elaboration to design potent nanomolar inhibitors against Mab TrmD. Several of these compounds exhibit promising activity against mycobacterial species, including Mycobacterium tuberculosis and Mycobacterium leprae in addition to Mab, supporting the use of TrmD as a target for the development of antimycobacterial compounds.
- Whitehouse, Andrew J.,Thomas, Sherine E.,Brown, Karen P.,Fanourakis, Alexander,Chan, Daniel S.-H.,Libardo, M. Daben J.,Mendes, Vitor,Boshoff, Helena I. M.,Floto, R. Andres,Abell, Chris,Blundell, Tom L.,Coyne, Anthony G.
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supporting information
p. 7210 - 7232
(2019/08/20)
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- ISOQUINOLINES AS INHIBITORS OF HPK1
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Isoquinoline compounds and their use as inhibitors of HPK1 (hematopoietic kinase 1) are described. The compounds are useful in treating HPK1-dependent disorders and enhancing an immune response. Also described are methods of inhibitng HPK1, methods of treating HPK1-dependent disorders, methods for enhancing an immune response, and methods for preparing the isoquinoline compounds.
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Paragraph 1565; 1566
(2018/10/21)
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- Modular Route to Azaindanes
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A convergent radical based route to azaindanes is described, relying on the degenerative addition transfer of various substituted S-(pyridylmethyl)-O-ethyl dithiocarbonates (xanthates) to functional alkenes followed by radical cyclization onto the pyridine ring activated by protonation with trifluoroacetic acid. In one case, a richly decorated cyclohepta[b]pyridine could be assembled swiftly by allowing the first adduct to N-phenylmaleimide to undergo addition to N-allylphthalimide prior to cyclization.
- Huang, Qi,Zard, Samir Z.
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supporting information
p. 3895 - 3898
(2017/07/26)
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- Structure-activity relationships (SAR) and structure-kinetic relationships (SKR) of sulphone-based CRTh2 antagonists
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Monocyclic and bicyclic ring systems were investigated as the "core" section of a series of diphenylsulphone-containing acetic acid CRTh2 receptor antagonists. A range of potencies were observed and single-digit nanomolar potencies were obtained in both the monocyclic and bicyclic cores. Residence times for the monocyclic compounds were very short. Some of the bicyclic cores displayed better residence times. A methyl group in the northern part of the core, between the head and tail was a necessary requirement for the beginnings of long residence times. Variations of the tail substitution maximised potencies and residence times.
- Buil, Maria Antonia,Calbet, Marta,Castillo, Marcos,Castro, Jordi,Esteve, Cristina,Ferrer, Manel,Forns, Pilar,González, Jacob,López, Sara,Roberts, Richard S.,Sevilla, Sara,Vidal, Bernat,Vidal, Laura,Vilaseca, Pere
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p. 102 - 133
(2016/03/04)
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- HETEROARYL COMPOUNDS USEFUL AS INHIBITORS OF SUMO ACTIVATING ENZYME
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Disclosed are compounds of formula (I): or a pharmaceutically acceptable salt thereof; wherein Y, Ra, Ra', Rc, Rf, X2, Rd, Rd', Re, Re', m, and G have the values described herein and stereochemical configurations depicted at asterisked positions indicate absolute stereochemistry, useful as inhibitors of Sumo Activating Enzyme (SAE). Further provided are pharmaceutical compositions comprising a compound of the disclosure and methods of using the compositions in the treatment of proliferative, inflammatory, cardiovascular and neurodegenerative diseases or disorders.
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Paragraph 00194
(2015/01/16)
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- Palladium-catalyzed arylation of aldehydes with bromo-substituted 1,3-diaryl-imidazoline carbene ligand
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The combination of 0 valent palladium precursor and bromo-substituted 1,3-diaryl-imidazoline carbene ligand precursor such as 1-(2-bromophenyl)-3-(2,6-diisopropylphenyl)-imidazolinium chloride 1a exhibited high catalytic activity for the 1,2-addition of arylboronic acids to aldehydes including aqueous formaldehyde.
- Yamamoto, Tetsuya,Furusawa, Takuma,Zhumagazin, Azamat,Yamakawa, Tetsu,Oe, Yohei,Ohta, Tetsuo
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- SULFONYLPIPERAZINE DERIVATIVES THAT INTERACT WITH GLUCOKINASE REGULATORY PROTEIN FOR THE TREATMENT OF DIABETES
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The present invention relates to compounds of Formula I, or pharmaceutically acceptable salts thereof, that interact with glucokinase regulatory protein. In addition, the present invention relates to methods of treating type 2 diabetes, and other diseases and/or conditions where glucokinase regulatory protein is involved using the compounds, or pharmaceutically acceptable salts thereof, and pharmaceutical compositions that contain the compounds, or pharmaceutically acceptable salts thereof.
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Page/Page column 571; 572
(2012/03/26)
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- HETEROCYCLIC DERIVED METALLOPROTEASE INHIBITORS
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This invention provides novel heterocyclic derived matrix metalloprotease inhibitors of the formula: and pharmaceutical compositions comprising same, useful for treating disorders ameliorated by antagonizing matrix metalloproteases. This invention also provides therapeutic and prophylactic methods using the instant pharmaceutical compositions.
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Page/Page column 47
(2008/06/13)
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- Syntheses and in vitro evaluation of arylsulfone-based MMP inhibitors with heterocycle-derived zinc-binding groups (ZBGs)
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Several classes of arylsulfone-based MMP-2/-9 inhibitors utilizing 6- to 8-membered heterocyclic rings as zinc-binding groups (ZBGs) have been synthesized and their enzyme inhibitory activities were evaluated. Although a number of 6- and 7-membered hetero
- Zhang, Yue-Mei,Fan, Xiaodong,Yang, Shyh-Ming,Scannevin, Robert H.,Burke, Sharon L.,Rhodes, Kenneth J.,Jackson, Paul F.
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p. 405 - 408
(2008/12/23)
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- NOVEL HERBICIDES
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Compounds of formula I: wherein R1, R2, R3, R4, m, R5, R6, n and Y are as defined in claim 1; or N-oxides, salts and optical isomers thereof. Furthermore, the present invention relates to processes for preparing compounds of formula (I), to herbicidal compositions comprising them and to methods of using them to control plants or to inhibit plant growth.
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Page/Page column 95
(2008/06/13)
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- Pyrazolones as inhibitors of 11B-hydroxysteroid dehydrogenase
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Provided herein are compounds of the formula (I): as well as pharmaceutically acceptable salts thereof, wherein the substituents are as those disclosed in the specification. These compounds, and the pharmaceutical compositions containing them, are useful for the treatment of diseases such as, for example, type II diabetes mellitus and metabolic syndrome.
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Page/Page column 38
(2008/06/13)
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- BENZAZEPINE DERIVATIVE, PROCESS FOR PRODUCING THE SAME, AND USE
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The present invention provides a novel benzazepine derivative represented by formula : wherein, R1 is a 5- or 6-membered aromatic ring, R2 is lower alkyl group, etc., Y is an optionally substituted imino group, ring A and ring B are independently an optionally substituted aromatic ring, W is formula -W1-X2-W2- (W1 and W2 are independently S(O)m1 (m1 is 0, 1 or 2), etc., and X2 is an optionally substituted alkylene groupetc. ), a preparation method and use thereof.
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Page 205-206
(2010/02/06)
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- Identification of MK-944a: A second clinical candidate from the hydroxylaminepentanamide isostere series of HIV protease inhibitors
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Recent results from human clinical trials have established the critical role of HIV protease inhibitors in the treatment of acquired immune-deficiency syndrome (AIDS). However, the emergence of viral resistance, demanding treatment protocols, and adverse side effects have exposed the urgent need for a second generation of HIV protease inhibitors. The continued exploration of our hydroxylaminepentanamide (HAPA) transition-state isostere series of HIV protease inhibitors, which initially resulted in the identification of Crixivan (indinavir sulfate, MK-639, L-735,524), has now yielded MK-944a (L-756,423). This compound is potent, is selective, and competitively inhibits HIV-1 PR with a K(i) value of 0.049 nM. It stops the spread of the HIV(IIIb)-infected MT4 lymphoid cells at 25.0-50.0 nM, even in the presence of α1 acid glycoprotein, human serum albumin, normal human serum, or fetal bovine serum. MK-944a has a longer half-life in several animal models (rats, dogs, and monkeys) than indinavir sulfate and is currently in advanced human clinical trials.
- Dorsey,McDonough,McDaniel,Levin,Newton,Hoffman,Darke,Zugay-Murphy,Emini,Schleif,Olsen,Stahlhut,Rutkowski,Kuo,Lin,Chen,Michelson,Holloway,Huff,Vacca
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p. 3386 - 3399
(2007/10/03)
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- Syntheses of ortho-hydroxymethylpyridinols and dioxaphosphorino[m,n-x]pyridines
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Dioxaphosphorino[m,n-x]pyridines compounds have been prepared by condensation of methyl dichlorophosphate with new ortho-hydroxymethylpyridinols.
- Leroy,Despres,Bigan,Blondeau
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p. 2257 - 2272
(2007/10/03)
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- Catalyzed Metalation Applied to 2-Methoxypyridine
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Directed ortho lithiation of 2-methoxypyridine (1) has been regioselectively achieved at position 3 by using methyllithium catalyzed by a small amount of diisopropylamine.This metalation methodology, called "catalyzed metalation", gave good results whereas other metalation routes failed.This allowed the convenient synthesis of various 3-substituted 2-methoxypyridines of general interest.
- Trecourt, F.,Mallet, M.,Marsais, F.,Queguiner, G.
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p. 1367 - 1371
(2007/10/02)
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