5-lipoxygenase-activating protein inhibitors: development of 3-[3-tert-butylsulfanyl-1-[4-(6-methoxy-pyridin-3-yl)-benzyl]-5-(pyridin-2-ylmethoxy)-1H-indol-2-yl]-2,2-dimethyl-propionic acid (AM103)

  • J Med Chem. 2009 Oct 8;52(19):5803-15. doi: 10.1021/jm900945d.
John H Hutchinson  1 ,  Yiwei Li ,  Jeannie M Arruda ,  Christopher Baccei ,  Gretchen Bain ,  Charles Chapman ,  Lucia Correa ,  Janice Darlington ,  Christopher D King ,  Catherine Lee ,  Dan Lorrain ,  Pat Prodanovich ,  Haojing Rong ,  Angelina Santini ,  Nicholas Stock ,  Peppi Prasit ,  Jilly F Evans
Affiliations
  • 1. Departments of Chemistry, Amira Pharmaceuticals, San Diego, California 92121, USA. [email protected]
PMID: 19739647 DOI: 10.1021/jm900945d
Abstract

The potent and selective 5-lipoxygenase-activating protein leukotriene synthesis inhibitor 3-[3-tert-butylsulfanyl-1-[4-(6-methoxy-pyridin-3-yl)-benzyl]-5-(pyridin-2-ylmethoxy)-1H-indol-2-yl]-2,2-dimethyl-propionic acid (11j) is described. Lead optimization was designed to afford compounds with superior in vitro and in vivo inhibition of leukotriene synthesis in addition to having excellent pharmacokinetics and safety in rats and dogs. The key structural features of these new compounds are incorporation of heterocycles on the indole N-benzyl substituent and replacement of the quinoline group resulting in compounds with excellent in vitro and in vivo activities, superior pharmacokinetics, and improved physical properties. The methoxypyridine derivative 11j has an IC(50) of 4.2 nM in a 5-lipoxygenase-activating protein (FLAP) binding assay, an IC(50) of 349 nM in the human blood LTB(4) inhibition assay, and is efficacious in a murine ovalbumin model of allergen-induced asthma. Compound 11j was selected for clinical development and has successfully completed phase 1 trials in healthy volunteers.

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