title: A conformationally constrained inhibitor with an enhanced potency for β-tryptase and stability against semicarbazide-sensitive amine oxidase (SSAO).
abstract: A novel β-tryptase inhibitor with a basic benzylamine P1 group, a piperidine-amide linker, and a substituted indole P4 group was discovered. A substitution at 4-indole position was introduced to constrain the conformational flexibility of the inhibitor to the bioactive conformation exhibited by X-ray structures so that entropic penalty was decreased. More importantly, this constrained conformation limited the accessibility of this molecule to anti-targets, especially SSAO, so that an enhanced metabolic profile was achieved.
authors.affiliation: Drug Design, Chemical and Analytical Science, Sanofi-Aventis Pharmaceuticals, Route 202-206, Bridgewater, NJ 08807, USA. guyan.liang@sanofi-aventis.com
authors.forename: Guyan
authors.initials: G
authors.lastname: Liang
authors.forename: Yong Mi
authors.initials: YM
authors.lastname: Choi-Sledeski
authors.forename: Gregory
authors.initials: G
authors.lastname: Poli
authors.forename: Xin
authors.initials: X
authors.lastname: Chen
authors.forename: Patrick
authors.initials: P
authors.lastname: Shum
authors.forename: Anne
authors.initials: A
authors.lastname: Minnich
authors.forename: Qingping
authors.initials: Q
authors.lastname: Wang
authors.forename: Joseph
authors.initials: J
authors.lastname: Tsay
authors.forename: Keith
authors.initials: K
authors.lastname: Sides
authors.forename: Jennifer
authors.initials: J
authors.lastname: Cairns
authors.forename: Gregory
authors.initials: G
authors.lastname: Stoklosa
authors.forename: Thaddeus
authors.initials: T
authors.lastname: Nieduzak
authors.forename: Zhicheng
authors.initials: Z
authors.lastname: Zhao
authors.forename: Jie
authors.initials: J
authors.lastname: Wang
authors.forename: Roy J
authors.initials: RJ
authors.lastname: Vaz
mesh_terms: D006631:Amine Oxidase (Copper-Containing) / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008968:Molecular Conformation; D056004:Molecular Dynamics Simulation; D053802:Tryptases / Q000037:antagonists & inhibitors*; D014961:X-Ray Diffraction
chemical_list: D004791:Enzyme Inhibitors; D006631:Amine Oxidase (Copper-Containing); D053802:Tryptases