A conformationally constrained inhibitor with an enhanced potency for β-tryptase and stability against semicarbazide-sensitive amine oxidase (SSAO).
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.
Liang
Guyan
G
Drug Design, Chemical and Analytical Science, Sanofi-Aventis Pharmaceuticals, Route 202-206, Bridgewater, NJ 08807, USA. guyan.liang@sanofi-aventis.com
Choi-Sledeski
Yong Mi
YM
Poli
Gregory
G
Chen
Xin
X
Shum
Patrick
P
Minnich
Anne
A
Wang
Qingping
Q
Tsay
Joseph
J
Sides
Keith
K
Cairns
Jennifer
J
Stoklosa
Gregory
G
Nieduzak
Thaddeus
T
Zhao
Zhicheng
Z
Wang
Jie
J
Vaz
Roy J
RJ
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
D004791:Enzyme Inhibitors; D006631:Amine Oxidase (Copper-Containing); D053802:Tryptases