Publication date: Jan 01, 2020
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.
Sutherland, H.S., Tong, A.S.T., Choi, P.J., Blaser, A., Franzblau, S.G., Cooper, C.B., Upton, A.M., Lotlikar, M., Denny, W.A., and Palmer, B.D. Variations in the C-unit of bedaquiline provides analogues with improved biology and pharmacology. 07505. 2020 Bioorg Med Chem (28):1.