221615-71-0Relevant articles and documents
Structure-activity relationships for unit C pyridyl analogues of the tuberculosis drug bedaquiline
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.
supporting information, p. 1283 - 1291 (2019/02/24)
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.
Catalytic Enantioselective Pyridine N-Oxidation
Hsieh, Sheng-Ying,Tang, Yu,Crotti, Simone,Stone, Elizabeth A.,Miller, Scott J.
, p. 18624 - 18629 (2019/11/21)
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.
5-HYDROXYPYRIMIDINE-4-CARBOXAMIDE COMPOUND
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Page/Page column 66, (2011/05/16)
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].
