- Structure-activity relationships for unit C pyridyl analogues of the tuberculosis drug bedaquiline
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The ATP-synthase inhibitor bedaquiline is effective against drug-resistant tuberculosis but is extremely lipophilic (clogP 7.25) with a very long plasma half-life. Additionally, inhibition of potassium current through the cardiac hERG channel by bedaquiline, is associated with prolongation of the QT interval, necessitating cardiovascular monitoring. Analogues were prepared where the naphthalene C-unit was replaced with substituted pyridines to produce compounds with reduced lipophilicity, anticipating a reduction in half-life. While there was a direct correlation between in vitro inhibitory activity against M. tuberculosis (MIC90) and compound lipophilicity, potency only fell off sharply below a clogP of about 4.0, providing a useful lower bound for analogue design. The bulk of the compounds remained potent inhibitors of the hERG potassium channel, with notable exceptions where IC50 values were at least 5-fold higher than that of bedaquiline. Many of the compounds had desirably higher rates of clearance than bedaquiline, but this was associated with lower plasma exposures in mice, and similar or higher MICs resulted in lower AUC/MIC ratios than bedaquiline for most compounds. The two compounds with lower potency against hERG exhibited similar clearance to bedaquiline and excellent efficacy in vivo, suggesting further exploration of C-ring pyridyls is worthwhile.
- Blaser, Adrian,Sutherland, Hamish S.,Tong, Amy S.T.,Choi, Peter J.,Conole, Daniel,Franzblau, Scott G.,Cooper, Christopher B.,Upton, Anna M.,Lotlikar, Manisha,Denny, William A.,Palmer, Brian D.
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supporting information
p. 1283 - 1291
(2019/02/24)
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- Structure-Activity Relationship Studies of Tolfenpyrad Reveal Subnanomolar Inhibitors of Haemonchus contortus Development
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Recently, we have discovered that the registered pesticide, tolfenpyrad, unexpectedly and potently inhibits the development of the L4 larval stage of the parasitic nematode Haemonchus contortus with an IC50 value of 0.03 μM while displaying good selectivity, with an IC50 of 37.9 μM for cytotoxicity. As a promising molecular template for medicinal chemistry optimization, we undertook anthelmintic structure-activity relationships for this chemical. Modifications of the left-hand side (LHS), right-hand side (RHS), and middle section of the scaffold were explored to produce a set of 57 analogues. Analogues 25, 29, and 33 were shown to be the most potent compounds of the series, with IC50 values at a subnanomolar level of potency against the chemotherapeutically relevant fourth larval (L4) stage of H. contortus. Selected compounds from the series also showed promising activity against a panel of other different parasitic nematodes, such as hookworms and whipworms.
- Le, Thuy G.,Kundu, Abhijit,Ghoshal, Atanu,Nguyen, Nghi H.,Preston, Sarah,Jiao, Yaqing,Ruan, Banfeng,Xue, Lian,Huang, Fei,Keiser, Jennifer,Hofmann, Andreas,Chang, Bill C. H.,Garcia-Bustos, Jose,Wells, Timothy N. C.,Palmer, Michael J.,Jabbar, Abdul,Gasser, Robin B.,Baell, Jonathan B.
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p. 1036 - 1053
(2019/01/14)
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- Catalytic Enantioselective Pyridine N-Oxidation
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The catalytic, enantioselective N-oxidation of substituted pyridines is described. The approach is predicated on a biomolecule-inspired catalytic cycle wherein high levels of asymmetric induction are provided by aspartic-acid-containing peptides as the aspartyl side chain shuttles between free acid and peracid forms. Desymmetrizations of bis(pyridine) substrates bearing a remote pro-stereogenic center substituted with a group capable of hydrogen bonding to the catalyst are demonstrated. Our approach presents a new entry into chiral pyridine frameworks in a heterocycle-rich molecular environment. Representative functionalizations of the enantioenriched pyridine N-oxides further document the utility of this approach. Demonstration of the asymmetric N-oxidation in two venerable drug-like scaffolds, Loratadine and Varenicline, show the likely generality of the method for highly variable and distinct chiral environments, while also revealing that the approach is applicable to both pyridines and 1,4-pyrazines.
- Hsieh, Sheng-Ying,Tang, Yu,Crotti, Simone,Stone, Elizabeth A.,Miller, Scott J.
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p. 18624 - 18629
(2019/11/21)
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- Phosphodiesterase inhibitors. Part 4: Design, synthesis and structure-activity relationships of dual PDE3/4-inhibitory fused bicyclic heteroaromatic-4,4-dimethylpyrazolones
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(-)-6-(7-Methoxy-2-trifluoromethylpyrazolo[1,5-a]pyridin-4-yl)-5-methyl-4, 5-dihydro-3-(2H)-pyridazinone (KCA-1490) is a dual PDE3/4 inhibitor that exhibits potent combined bronchodilatory and anti-inflammatory activity. Here we show that a 4,4-dimethylpyrazolone subunit serves as an effective surrogate for the 5-methyl-4,5-dihydropyridazin-3(2H)-one ring of KCA-1490 whilst lacking a stereogenic centre. The 2- and 7-substituents in the pyrazolo[1,5-a]pyridine subunit markedly influence the PDE-inhibitory profile and can be adjusted to afford either potent PDE4-selective inhibitors or dual PDE3/4 inhibitors. A survey of bicyclic heteroaromatic replacements for the pyrazolo[1,5-a]pyridine allowed further refinement of the inhibitory profile and identified 3-(8-methoxy-2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl)-4, 4-dimethyl-1H-pyrazol-5(4H)-one as an orally active, achiral KCA-1490 analog with well-balanced dual PDE3/4-inhibitory activity.
- Ochiai, Koji,Takita, Satoshi,Kojima, Akihiko,Eiraku, Tomohiko,Ando, Naoki,Iwase, Kazuhiko,Kishi, Tetsuya,Ohinata, Akira,Yageta, Yuichi,Yasue, Tokutaro,Adams, David R.,Kohno, Yasushi
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supporting information
p. 5833 - 5838
(2012/11/07)
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- KYNURENINE PRODUCTION INHIBITOR
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Provided is a kynurenine production inhibitor comprising a nitrogen-containing heterocyclic compound represented by formula (I): (wherein R50 and R51 may be the same or different and each represent a hydrogen atom or the like, G1 and G2 may be the same or different and each represent a nitrogen atom or the like, X represents formula (III): (wherein m1 and m2 may be the same or different and each represent an integer of 0 or 1, Y represents an oxygen atom or the like, and R6 and R7 may be the same or different and each represent a hydrogen atom or the like), R1 represents optionally substituted lower alkyl or the like, R2 represents a hydrogen atom or the like, and R3 represents optionally substituted lower alkyl or the like), and the like.
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Page/Page column 133-134
(2011/10/12)
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- 5-HYDROXYPYRIMIDINE-4-CARBOXAMIDE COMPOUND
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The present invention provides compounds which promote erythropoietin production. Compounds represented by the following general formula (1) or pharmacologically acceptable salts thereof are provided: [wherein, R1 represents a group —X-Q1, X-Q1-Y-Q2 or X-Q1-Y-Q2-Z-Q3, X represents a single bond, —CH2— or the like, Q1 represents a monocyclic or bicyclic heterocyclic group which may have substituent(s), Y represents a single bond, —CH2—, or the like, Q2 represents a monocyclic or bicyclic hydrocarbon ring group which may have substituent(s) or a monocyclic or bicyclic heterocyclic group which may have substituent(s), Z represents a single bond, —CR11R12— or the like, R11 and R12 each independently represents a hydrogen atom, a halogen atom or the like, Q3 represents a phenyl group which may have substituent(s), a C3-C7 cycloalkyl group which may have substituent(s), a C3-C7 cycloalkenyl group which may have substituent(s) or a monocyclic or bicyclic heterocyclic group which may have substituent(s), R2 represents a C1-C3 alkyl group or the like, and R3 represents a hydrogen atom or a methyl group].
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Page/Page column 66
(2011/05/16)
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- SUBSTITUTED PYRIDYLMETHYL BICYCLOCARBOXYAMIDE COMPOUNDS
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This invention provides a compound of the formula (I): wherein A1 is N and A2 is CR7, or A1 is CR7 and A2 is N; Y1, Y2 and Y3 are each independently CH or N, Y4 and Y5 are each independently CR8 or N, with the proviso that when one of Y1, Y2, Y3, Y4 and Y5 is N, the others are not N; R1 and R2 are each independently hydrogen, halogen, (C1-C6)alkyl, halo(C1-C6)alkyl or hydroxy(C1-C6)alkyl; R3 and R8 are each independently hydrogen, halogen, hydroxy, (C1-C6)alkyl, hydroxy(C1-C6)alkoxy, (C1-C6)alkoxy-(C1-C6)alkyl, (C1-C6)alkoxy-(C1-C6)alkoxy, halo(C1-C6)alkyl, (C1-C6)alkylthio, (C1-C6)alkylsulfinyl or (C1-C6)alkylsulfonyl; R4 is halogen, (C1-C6)alkyl, (C3-C6)cycloalkyl, halo(C1-C6)alkyl, hydroxy(C1-C6)alkyl, halo(C1-C6)alkoxy, hydroxy(C1-C6)alkoxy, (C1-C6)alkoxy-(C1-C6)alkyl, (C1-C6)aIkoxy-(C1-C6)alkoxy, halo(C1-C6)alkylsuIfonyl, halo(C1-C6)alkylsulfinyl, halo(C1-C6)alkylthio, [(C1-C6)alkyl]NH- or [(C1-C6)alkyl]2N-; and R5, R6 and R7 are each independently hydrogen, halogen, (C1-C6)alkyl, hydroxy(C1-C6)alkyI, or (C1-C6)alkoxy; or a pharmaceutically acceptable salt, solvate thereof. These compounds are useful for the treatment of disease conditions caused by overactivation of the VR1 receptor such as pain, or the like in mammal. This invention also provides a pharmaceutical composition comprising the above compound.
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Page/Page column 37-38
(2008/06/13)
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- PYRAZOLOPYRIDINE DERIVATES
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New compounds of formula (I) and the salts, solvates and prodrugs thereof, wherein the meanings for the various substituents are as disclosed in the description. These compounds are useful as p38 kinase inhibitors.
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- Process for making diaryl pyridines useful as cox-2 inhibitors
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The invention encompasses a process for making compounds of Formula I useful in the treatment of cyclooxygenase-2 mediated diseases.
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Page column 14-15
(2010/01/31)
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- A practical synthesis of a COX-2-specific inhibitor
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A number of synthetic strategies to the Cox-2 specific inhibitor 1 have been described. These studies have led to the identification of a novel pyridine construction using annulation of ketone 2 using a vinamidinium species 29 and ammonia in 97% assay yield. Three approaches to the synthesis of ketone 2 are described that allow for its preparation in large quantities in >65% overall yield from methyl 6-methylnicotinate.
- Davies,Marcoux,Corley,Journet,Cai,Palucki,Wu,Larsen,Rossen,Pye,DiMichele,Dormer,Reider
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p. 8415 - 8420
(2007/10/03)
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- A concise route to novel 1-aryl and 1-pyridyl-2-azabicyclo[2.1.1]hexanes
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A number of novel 1-aryl and 1-pyridyl-2-azabicyclo[2.1.1]hexane derivatives were prepared by an intramolecular [2+2] photocycloaddition in the presence of acetophenone as the sensitizer. Substitution of the azabicyclo[2.1.1]hexane ring was accomplished by appropriate choice of the heteroaryl ketone and allylamine starting materials. Several aryl 9a-e, g and pyridyl analogs 9h-l were prepared by this method. The structures of 9a and 9i were verified by X-ray crystallography. Several of the photoproducts 9 were converted into the corresponding N-Me and N-H 2,4-methanonicotine analogs 4 by reduction or hydrolysis of the N-carboethoxy group.
- Piotrowski, David W.
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p. 1091 - 1093
(2007/10/03)
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