Spirocycle MmpL3 Inhibitors with Improved hERG and Cytotoxicity Profiles as Inhibitors of Mycobacterium tuberculosis Growth.

Autor:	Ray PC; Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, Dundee DD1 5EH, U.K., Huggett M; Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, Dundee DD1 5EH, U.K., Turner PA; Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, Dundee DD1 5EH, U.K., Taylor M; Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, Dundee DD1 5EH, U.K., Cleghorn LAT; Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, Dundee DD1 5EH, U.K., Early J; TB Discovery Research, Infectious Disease Research Institute, 1616 Eastlake Avenue East, Suite 400, Seattle, Washington 98102, United States., Kumar A; TB Discovery Research, Infectious Disease Research Institute, 1616 Eastlake Avenue East, Suite 400, Seattle, Washington 98102, United States., Bonnett SA; TB Discovery Research, Infectious Disease Research Institute, 1616 Eastlake Avenue East, Suite 400, Seattle, Washington 98102, United States., Flint L; TB Discovery Research, Infectious Disease Research Institute, 1616 Eastlake Avenue East, Suite 400, Seattle, Washington 98102, United States., Joerss D; TB Discovery Research, Infectious Disease Research Institute, 1616 Eastlake Avenue East, Suite 400, Seattle, Washington 98102, United States., Johnson J; TB Discovery Research, Infectious Disease Research Institute, 1616 Eastlake Avenue East, Suite 400, Seattle, Washington 98102, United States., Korkegian A; TB Discovery Research, Infectious Disease Research Institute, 1616 Eastlake Avenue East, Suite 400, Seattle, Washington 98102, United States., Mullen S; TB Discovery Research, Infectious Disease Research Institute, 1616 Eastlake Avenue East, Suite 400, Seattle, Washington 98102, United States., Moure AL; Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, Dundee DD1 5EH, U.K., Davis SH; Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, Dundee DD1 5EH, U.K., Murugesan D; Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, Dundee DD1 5EH, U.K., Mathieson M; Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, Dundee DD1 5EH, U.K., Caldwell N; Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, Dundee DD1 5EH, U.K., Engelhart CA; Department of Microbiology and Immunology, Weill Cornell Medical College, New York, New York 10065, United States., Schnappinger D; Department of Microbiology and Immunology, Weill Cornell Medical College, New York, New York 10065, United States., Epemolu O; Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, Dundee DD1 5EH, U.K., Zuccotto F; Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, Dundee DD1 5EH, U.K., Riley J; Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, Dundee DD1 5EH, U.K., Scullion P; Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, Dundee DD1 5EH, U.K., Stojanovski L; Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, Dundee DD1 5EH, U.K., Massoudi L; Mycobacteria Research Laboratories, Colorado State University, 200 W. Lake Street, Fort Collins, Colorado 80523-1682, United States., Robertson GT; Mycobacteria Research Laboratories, Colorado State University, 200 W. Lake Street, Fort Collins, Colorado 80523-1682, United States., Lenaerts AJ; Mycobacteria Research Laboratories, Colorado State University, 200 W. Lake Street, Fort Collins, Colorado 80523-1682, United States., Freiberg G; AbbVie, 1 North Waukegan Road, North Chicago, Illinois 60064, United States., Kempf DJ; AbbVie, 1 North Waukegan Road, North Chicago, Illinois 60064, United States., Masquelin T; Discovery Chemistry Research, Eli Lilly and Company, Lilly Corporate Centre, MC/87/02/203, G17, Indianapolis, Indiana 46285, United States., Hipskind PA; Lgenia Inc., Fortville, Indiana 46040, United States., Odingo J; TB Discovery Research, Infectious Disease Research Institute, 1616 Eastlake Avenue East, Suite 400, Seattle, Washington 98102, United States., Read KD; Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, Dundee DD1 5EH, U.K., Green SR; Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, Dundee DD1 5EH, U.K., Wyatt PG; Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, Dundee DD1 5EH, U.K., Parish T; TB Discovery Research, Infectious Disease Research Institute, 1616 Eastlake Avenue East, Suite 400, Seattle, Washington 98102, United States.
Jazyk:	angličtina
Zdroj:	ACS omega [ACS Omega] 2021 Jan 13; Vol. 6 (3), pp. 2284-2311. Date of Electronic Publication: 2021 Jan 13 (Print Publication: 2021).
DOI:	10.1021/acsomega.0c05589
Abstrakt:	With the emergence of multi-drug-resistant strains of Mycobacterium tuberculosis, there is a pressing need for new oral drugs with novel mechanisms of action. A number of scaffolds with potent anti-tubercular in vitro activity have been identified from phenotypic screening that appear to target MmpL3. However, the scaffolds are typically lipophilic, which facilitates partitioning into hydrophobic membranes, and several contain basic amine groups. Highly lipophilic basic amines are typically cytotoxic against mammalian cell lines and have associated off-target risks, such as inhibition of human ether-à-go-go related gene (hERG) and IKr potassium current modulation. The spirocycle compound 3 was reported to target MmpL3 and displayed promising efficacy in a murine model of acute tuberculosis (TB) infection. However, this highly lipophilic monobasic amine was cytotoxic and inhibited the hERG ion channel. Herein, the related spirocycles ( 1-2 ) are described, which were identified following phenotypic screening of the Eli Lilly corporate library against M. tuberculosis . The novel N-alkylated pyrazole portion offered improved physicochemical properties, and optimization led to identification of a zwitterion series, exemplified by lead 29 , with decreased HepG2 cytotoxicity as well as limited hERG ion channel inhibition. Strains with mutations in MmpL3 were resistant to 29 , and under replicating conditions, 29 demonstrated bactericidal activity against M. tuberculosis . Unfortunately, compound 29 had no efficacy in an acute model of TB infection; this was most likely due to the in vivo exposure remaining above the minimal inhibitory concentration for only a limited time. Competing Interests: The authors declare no competing financial interest. (© 2021 The Authors. Published by American Chemical Society.)
Databáze:	MEDLINE
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