title: Structure-based library design and the discovery of a potent and selective mast cell β-tryptase inhibitor as an oral therapeutic agent.
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.
authors.affiliation: Molecular Innovative Therapeutics, Sanofi Pharmaceuticals, USA. guyan.liang@sanofi.com
authors.forename: Guyan
authors.initials: G
authors.lastname: Liang
authors.forename: Suzanne
authors.initials: S
authors.lastname: Aldous
authors.forename: Gregory
authors.initials: G
authors.lastname: Merriman
authors.forename: Julian
authors.initials: J
authors.lastname: Levell
authors.forename: James
authors.initials: J
authors.lastname: Pribish
authors.forename: Jennifer
authors.initials: J
authors.lastname: Cairns
authors.forename: Xin
authors.initials: X
authors.lastname: Chen
authors.forename: Sebastien
authors.initials: S
authors.lastname: Maignan
authors.forename: Magali
authors.initials: M
authors.lastname: Mathieu
authors.forename: Joseph
authors.initials: J
authors.lastname: Tsay
authors.forename: Keith
authors.initials: K
authors.lastname: Sides
authors.forename: Sam
authors.initials: S
authors.lastname: Rebello
authors.forename: Brian
authors.initials: B
authors.lastname: Whitely
authors.forename: Isabelle
authors.initials: I
authors.lastname: Morize
authors.forename: Henry W
authors.initials: HW
authors.lastname: Pauls
mesh_terms: D000284:Administration, Oral; D000818:Animals; D020650:Combinatorial Chemistry Techniques; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology*; D006801:Humans; D008407:Mast Cells / Q000201:enzymology*; D008958:Models, Molecular; D015394:Molecular Structure; D051381:Rats; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors; D054852:Small Molecule Libraries / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D053802:Tryptases / Q000037:antagonists & inhibitors*
chemical_list: D004791:Enzyme Inhibitors; D011994:Recombinant Proteins; D054852:Small Molecule Libraries; D053802:Tryptases