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Variations in the C-unit of bedaquiline provides analogues with improved biology and pharmacology.
Sutherland, Hamish S; Tong, Amy S T; Choi, Peter J; Blaser, Adrian; Franzblau, Scott G; Cooper, Christopher B; Upton, Anna M; Lotlikar, Manisha; Denny, William A; Palmer, Brian D.
Afiliação
  • Sutherland HS; Auckland Cancer Society Research Centre, School of Medical Sciences, and Maurice Wilkins Centre, University of Auckland, Private Bag 92019, Auckland 1142, New Zealand.
  • Tong AST; Auckland Cancer Society Research Centre, School of Medical Sciences, and Maurice Wilkins Centre, University of Auckland, Private Bag 92019, Auckland 1142, New Zealand.
  • Choi PJ; Auckland Cancer Society Research Centre, School of Medical Sciences, and Maurice Wilkins Centre, University of Auckland, Private Bag 92019, Auckland 1142, New Zealand.
  • Blaser A; Auckland Cancer Society Research Centre, School of Medical Sciences, and Maurice Wilkins Centre, University of Auckland, Private Bag 92019, Auckland 1142, New Zealand.
  • Franzblau SG; Institute for Tuberculosis Research, College of Pharmacy, University of Illinois at Chicago, 833 South Wood Street, Chicago, IL 60612, USA.
  • Cooper CB; Global Alliance for TB Drug Development, 40 Wall St, New York, NY 10005, USA.
  • Upton AM; Global Alliance for TB Drug Development, 40 Wall St, New York, NY 10005, USA.
  • Lotlikar M; Global Alliance for TB Drug Development, 40 Wall St, New York, NY 10005, USA.
  • Denny WA; Auckland Cancer Society Research Centre, School of Medical Sciences, and Maurice Wilkins Centre, University of Auckland, Private Bag 92019, Auckland 1142, New Zealand; Maurice Wilkins Centre, University of Auckland, Private Bag 92019, Auckland 1142, New Zealand. Electronic address: b.denny@auckland.
  • Palmer BD; Auckland Cancer Society Research Centre, School of Medical Sciences, and Maurice Wilkins Centre, University of Auckland, Private Bag 92019, Auckland 1142, New Zealand; Maurice Wilkins Centre, University of Auckland, Private Bag 92019, Auckland 1142, New Zealand.
Bioorg Med Chem ; 28(1): 115213, 2020 01 01.
Article em En | MEDLINE | ID: mdl-31810890
ABSTRACT
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.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Diarilquinolinas / Mycobacterium tuberculosis / Antituberculosos Limite: Animals / Humans Idioma: En Ano de publicação: 2020 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Diarilquinolinas / Mycobacterium tuberculosis / Antituberculosos Limite: Animals / Humans Idioma: En Ano de publicação: 2020 Tipo de documento: Article