Metabolism-guided development of Ko143 analogs as ABCG2 inhibitors

Eur J Med Chem. 2023 Nov 5:259:115666. doi: 10.1016/j.ejmech.2023.115666. Epub 2023 Jul 20.

Abstract

ATP-binding cassette subfamily G member 2 (ABCG2), an efflux transporter, is involved in multiple pathological processes. Ko143 is a potent ABCG2 inhibitor; however, it is quickly metabolized through carboxylesterase 1-mediated hydrolysis of its t-butyl ester moiety. The current work aimed to develop more metabolically stable ABCG2 inhibitors. Novel Ko143 analogs were designed and synthesized by replacing the unstable t-butyl ester moiety in Ko143 with an amide group. The synthesized Ko143 analogs were evaluated for their ABCG2 inhibitory activity, binding mode with ABCG2, cytotoxicity, and metabolic stability. We found that the amide modification of Ko143 led to metabolically stable ABCG2 inhibitors. Among these Ko143 analogs, K2 and K34 are promising candidates with favorable oral pharmacokinetic profiles in mice. In summary, we synthesized novel Ko143 analogs with improved metabolic stability, which can potentially be used as lead compounds for the future development of ABCG2 inhibitors.

Keywords: ABCG2 inhibitor; Carboxylesterase; Ko143 analogs; Metabolic stability; Pharmacokinetics.

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily G, Member 2* / antagonists & inhibitors
  • ATP-Binding Cassette Transporters / antagonists & inhibitors
  • Animals
  • Biological Transport
  • Membrane Transport Proteins* / metabolism
  • Mice

Substances

  • ATP-Binding Cassette Transporters
  • Membrane Transport Proteins
  • 3-(6-isobutyl-9-methoxy-1,4-dioxo-1,2,3,4,6,7,12,12a-octahydropyrazino(1',2'-1,6)pyrido(3,4-b)indol-3-yl)propionic acid tert-butyl ester
  • ATP Binding Cassette Transporter, Subfamily G, Member 2