ABSTRACT
Tropanylamide was investigated as a possible scaffold for ß-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.
Subject(s)
Benzylamines/chemistry , Enzyme Inhibitors/chemistry , Ether-A-Go-Go Potassium Channels/metabolism , Thiophenes/chemistry , Tryptases/antagonists & inhibitors , Benzylamines/pharmacology , Crystallography, X-Ray , Drug Stability , ERG1 Potassium Channel , Enzyme Inhibitors/metabolism , Enzyme Inhibitors/pharmacology , Humans , Models, Molecular , Molecular Dynamics Simulation , Protein Binding/drug effects , Thiophenes/pharmacologyABSTRACT
A novel ß-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.
Subject(s)
Amine Oxidase (Copper-Containing)/antagonists & inhibitors , Enzyme Inhibitors/pharmacology , Tryptases/antagonists & inhibitors , Amine Oxidase (Copper-Containing)/metabolism , Animals , Enzyme Inhibitors/chemistry , Humans , Molecular Conformation , Molecular Dynamics Simulation , X-Ray DiffractionABSTRACT
The discovery and SAR of ketopiperazino methylazaindole factor Xa inhibitors are described. Structure-activity data suggesting that this class of inhibitors does not bind in the canonical mode were confirmed by an X-ray crystal structure showing the neutral haloaromatic bound in the S(1) subsite. The most potent azaindole, 33 (RPR209685), is selective against related serine proteases and attains higher levels of exposure upon oral dosing than comparable benzamidines and benzamidine isosteres. Compound 33 was efficacious in the canine AV model of thrombosis.
