Discovery of biaryl inhibitors of H+/K+ ATPase

Neil Garton; Nick Bailey; Mark Bamford; Emmanuel Demont; Irene Farre-Gutierrez; Gail Hutley; Gianpaolo Bravi; Paula Pickering

doi:10.1016/j.bmcl.2009.12.040

Discovery of biaryl inhibitors of H+/K+ ATPase

Bioorg Med Chem Lett. 2010 Feb 1;20(3):1049-54. doi: 10.1016/j.bmcl.2009.12.040. Epub 2009 Dec 21.

Authors

Neil Garton¹, Nick Bailey, Mark Bamford, Emmanuel Demont, Irene Farre-Gutierrez, Gail Hutley, Gianpaolo Bravi, Paula Pickering

Affiliation

¹ GlaxoSmithKline, Medicinal Chemistry, New Frontiers Science Park, Third Avenue, Harlow, Essex CM19 5AW, UK. [email protected]

PMID: 20053560
DOI: 10.1016/j.bmcl.2009.12.040

Abstract

We report the identification of a novel biaryl template for H(+)/K(+) ATPase inhibition. Evaluation of critical SAR features within the biaryl imidazole framework and the use of pharmacophore modelling against known imidazopyridine and azaindole templates suggested that the geometry of the molecule is key to achieving activity. Herein we present our work optimising the potency of the molecule through modifications and substitutions to each of the ring systems. In particular sub-micromolar potency is achieved with (4b) presumably through a proposed intramolecular hydrogen bond that ensures the required imidazole basic centre is appropriately located.

Publication types

Comparative Study
Research Support, Non-U.S. Gov't

MeSH terms

Drug Discovery / methods*
H(+)-K(+)-Exchanging ATPase / metabolism
Imidazoles / chemistry*
Imidazoles / metabolism
Imidazoles / pharmacology
Proton Pump Inhibitors*
Structure-Activity Relationship

Substances

Imidazoles
Proton Pump Inhibitors
H(+)-K(+)-Exchanging ATPase