Variations in the C-unit of bedaquiline provides analogues with improved biology and pharmacology.


:Analogues of the anti-tuberculosis drug bedaquiline, bearing a 3,5-dimethoxy-4-pyridyl C-unit, retain high anti-bacterial potency yet exert less inhibition of the hERG potassium channel, in vitro, than the parent compound. Two of these analogues (TBAJ-587 and TBAJ-876) are now in preclinical development. The present study further explores structure-activity relationships across a range of related 3,5-disubstituted-4-pyridyl C-unit bedaquiline analogues of greatly varying lipophilicity (clogP from 8.16 to 1.89). This broader class shows similar properties to the 3,5-dimethoxy-4-pyridyl series, being substantially more potent in vitro and equally active in an in vivo (mouse) model than bedaquiline, while retaining a lower cardiovascular risk profile through greatly attenuated hERG inhibition.


Bioorg Med Chem


Sutherland HS,Tong AST,Choi PJ,Blaser A,Franzblau SG,Cooper CB,Upton AM,Lotlikar M,Denny WA,Palmer BD




Has Abstract


2020-01-01 00:00:00














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