Alison Brownlie-Cutts

Publications (2)5.3 Total impact

• Article: Discovery of benzylisothioureas as potent divalent metal transporter 1 (DMT1) inhibitors.

  Zaihui Zhang, Vishnumurthy Kodumuru, Serguei Sviridov, Shifeng Liu, Mikhail Chafeev, Sultan Chowdhury, Nagasree Chakka, Jianyu Sun, Simon J Gauthier, Maryanne Mattice, Laszlo G Ratkay, Rainbow Kwan, Jay Thompson, Alison Brownlie Cutts, Jianmin Fu, Rajender Kamboj, Y Paul Goldberg, Jay A Cadieux
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  ABSTRACT: Inhibition of intestinal brush border DMT1 offers a novel therapeutic approach to the prevention and treatment of disorders of iron overload. Several series of diaryl and tricyclic benzylisothiourea compounds as novel and potent DMT1 inhibitors were discovered from the original hit compound 1. These compounds demonstrated in vitro potency against DMT1, desirable cell permeability properties and a dose-dependent inhibition of iron uptake in an acute rat model of iron hyperabsorption. Tricyclic compounds increased the in vitro potency by up to 16-fold versus the original hit. Diaryl compounds 6b and 14a demonstrated significant iron absorption inhibition in vivo with both 25 and 50 mg/kg doses. The diaryl and tricyclic compounds described in this report represent promising structural templates for further optimization.
  Bioorganic & medicinal chemistry letters 06/2012; 22(15):5108-13. · 2.65 Impact Factor
• Article: Synthesis and biological evaluation of substituted pyrazoles as blockers of divalent metal transporter 1 (DMT1).

  Jay A Cadieux, Zaihui Zhang, Maryanne Mattice, Alison Brownlie-Cutts, Jianmin Fu, Laszlo G Ratkay, Rainbow Kwan, Jay Thompson, Joseph Sanghara, Jing Zhong, Y Paul Goldberg
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  ABSTRACT: Three distinct series of substituted pyrazole blockers of divalent metal transporter 1 (DMT1) were elaborated from the high-throughput screening pyrazolone hit 1. Preliminary hit-to-lead efforts revealed a preference for electron-withdrawing substituents in the 4-amido-5-hydroxypyrazole series 6a-l. In turn, this preference was more pronounced in a series of 4-aryl-5-hydroxypyrazoles 8a-j. The representative analogs 6f and 12f were found to be efficacious in a rodent model of acute iron hyperabsorption. These three series represent promising starting points for lead optimization efforts aimed at the discovery of DMT1 blockers as iron overload therapeutics.
  Bioorganic & medicinal chemistry letters 11/2011; 22(1):90-5. · 2.65 Impact Factor