Structure-based library design and the discovery of a potent and selective mast cell β-tryptase inhibitor as an oral therapeutic agent

  • Bioorg Med Chem Lett. 2012 Jan 15;22(2):1049-54. doi: 10.1016/j.bmcl.2011.11.119.
Guyan Liang  1 ,  Suzanne Aldous ,  Gregory Merriman ,  Julian Levell ,  James Pribish ,  Jennifer Cairns ,  Xin Chen ,  Sebastien Maignan ,  Magali Mathieu ,  Joseph Tsay ,  Keith Sides ,  Sam Rebello ,  Brian Whitely ,  Isabelle Morize ,  Henry W Pauls
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PMID: 22192588 DOI: 10.1016/j.bmcl.2011.11.119
Abstract

A solid phase combinatorial library was designed based on X-ray structures and in-silico models to explore an inducible S4+ pocket, which is formed by a simple side-chain rotation of Tyr95. This inducible S4+ pocket is unique to β-tryptase and does not exist for Other trypsin-like serine proteases of interest. Therefore, inhibitors utilizing this pocket have inherent advantages for being selective against Other proteases in the same family. A member of this library was found to be a potent and selective β-tryptase inhibitor with a suitable pharmacokinetic profile for further clinical evaluation.

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