title: A β-tryptase inhibitor with a tropanylamide scaffold to improve in vitro stability and to lower hERG channel binding affinity.
abstract: Tropanylamide was investigated as a possible scaffold for β-tryptase inhibitors with a basic benzylamine P1 group and a substituted thiophene P4 group. Comparing to piperidinylamide, the tropanylamide scaffold is much more rigid, which presents less opportunity for the inhibitor to bind with off-target proteins, such as cytochrome P450, SSAO, and hERG potassium channel. The proposed binding mode was further confirmed by an in-house X-ray structure through co-crystallization.
authors.affiliation: Molecular Innovative Therapeutics, Sanofi Pharmaceuticals, 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: Patrick
authors.initials: P
authors.lastname: Shum
authors.forename: Xin
authors.initials: X
authors.lastname: Chen
authors.forename: Gregory B
authors.initials: GB
authors.lastname: Poli
authors.forename: Vasant
authors.initials: V
authors.lastname: Kumar
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: Jiesheng
authors.initials: J
authors.lastname: Kang
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhang
mesh_terms: D001596:Benzylamines / Q000737:chemistry* / Q000494:pharmacology; D018360:Crystallography, X-Ray; D004355:Drug Stability; D000072237:ERG1 Potassium Channel; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D051638:Ether-A-Go-Go Potassium Channels / Q000378:metabolism*; D006801:Humans; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D011485:Protein Binding / Q000187:drug effects; D013876:Thiophenes / Q000737:chemistry* / Q000494:pharmacology; D053802:Tryptases / Q000037:antagonists & inhibitors*
chemical_list: D001596:Benzylamines; D000072237:ERG1 Potassium Channel; D004791:Enzyme Inhibitors; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; D013876:Thiophenes; C572432:tropanylamide; D053802:Tryptases