2. Academic Validation
  3. Systematic evaluation of structure-property relationships and pharmacokinetics in 6-(hetero)aryl-substituted matched pair analogs of amiloride and 5-(N,N-hexamethylene)amiloride

Systematic evaluation of structure-property relationships and pharmacokinetics in 6-(hetero)aryl-substituted matched pair analogs of amiloride and 5-(N,N-hexamethylene)amiloride

  • Bioorg Med Chem. 2021 May 1;37:116116. doi: 10.1016/j.bmc.2021.116116.
Benjamin J Buckley 1,  Ashraf Aboelela 2,  Hiwa Majed 2,  Richard S Bujaroski 2,  Karen L White 3,  Andrew K Powell 3,  Wen Wang 3,  Kasiram Katneni 3,  Jessica Saunders 3,  David M Shackleford 3,  Susan A Charman 3,  Gregory M Cook 4,  Michael J Kelso 5,  Marie Ranson 6
Affiliations

Affiliations

  • 1 Illawarra Health and Medical Research Institute, Wollongong, NSW 2522, Australia; School of Chemistry and Molecular Bioscience, University of Wollongong, NSW 2522, Australia; Molecular Horizons, University of Wollongong, NSW 2522, Australia; CONCERT-Translational Cancer Research Centre, NSW 2750, Australia. Electronic address: bbuckley@uow.edu.au.
  • 2 School of Chemistry and Molecular Bioscience, University of Wollongong, NSW 2522, Australia; Molecular Horizons, University of Wollongong, NSW 2522, Australia.
  • 3 Centre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences, Monash University, VIC 3052, Australia.
  • 4 Department of Microbiology and Immunology, University of Otago, Otago 9016, New Zealand.
  • 5 Illawarra Health and Medical Research Institute, Wollongong, NSW 2522, Australia; School of Chemistry and Molecular Bioscience, University of Wollongong, NSW 2522, Australia; Molecular Horizons, University of Wollongong, NSW 2522, Australia.
  • 6 Illawarra Health and Medical Research Institute, Wollongong, NSW 2522, Australia; School of Chemistry and Molecular Bioscience, University of Wollongong, NSW 2522, Australia; Molecular Horizons, University of Wollongong, NSW 2522, Australia; CONCERT-Translational Cancer Research Centre, NSW 2750, Australia.
PMID: 33799173 DOI: 10.1016/j.bmc.2021.116116
Abstract

The K+-sparing diuretic amiloride elicits Anticancer activities in multiple animal models. During our recent medicinal chemistry campaign aiming to identify amiloride analogs with improved properties for potential use in Cancer, we discovered novel 6-(hetero)aryl-substituted amiloride and 5-(N,N-hexamethylene)amiloride (HMA) analogs with up to 100-fold higher potencies than the parent compounds against urokinase plasminogen activator (uPA), one of amiloride's putative Anticancer targets, and no diuretic or antikaliuretic effects. Here, we report the systematic evaluation of structure-property relationships (lipophilicity, aqueous solubility and in vitro metabolic stability in human and mouse liver microsomes) in twelve matched pair analogs selected from our 6-substituted amiloride and HMA libraries. Mouse plasma stability, plasma protein binding, Caco-2 cell permeability, cardiac ion channel activity and pharmacokinetics in mice (PO and IV) and rats (IV) are described alongside amiloride and HMA comparators for a subset of the four most promising matched-pair analogs. The findings combined with earlier uPA activity/selectivity and other data ultimately drove selection of two analogs (AA1-39 and AA1-41) that showed efficacy in separate mouse Cancer metastasis studies.

Keywords

Amiloride; Antimetastatic; Cancer; Lead optimization; Metastasis; SOSA; Selective optimization of side activity; Urokinase; uPA.

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