Structure based design of 4-(3-aminomethylphenyl)piperidinyl-1-amides: novel, potent, selective, and orally bioavailable inhibitors of βII tryptase

Neutrophil elastase reduces secretion of secretory leukoproteinase inhibitor (SLPI) by lung epithelial cells: role of charge of the proteinase-inhibitor complex

“…The modelling procedure involved the use of the X-ray crystal structure of SLPI with chymotrypsin (structure file kindly provided by Professor Wolfram Bode as described previously[ 33 ]) as a template to construct analogous complexes with other proteinases. X-ray crystal structures of NE (PDB ID 1H1B; [ 42 ]), CG(PDB ID 1T32;[ 43 ]), trypsin (PDB ID 1TX6;[ 44 ]), mast cell chymase (PDB ID 1T31;[ 43 ]) and mast cell tryptase (PDB ID 2BM2;[ 45 ]) were obtained from the Research Collaboratory for Structural Bioinformatics Protein Data Bank[ 46 ] . These structures were then superimposed on the proteinase in the SLPI-proteinase complex using SWISSPDB[ 47 ] .…”

Mast Cell Tryptase β as a Target in Allergic Inflammation: An Evolving Story

“…These include structurally diverse ligands such as the 2-azepanone derivative 18 (IC 50 38 nM) [137], the 4-amidino-benzoic acid derivative 19 (K i 84 nM) [138], as well as gabexate mesylate (20, K i 3.4 nM) [139] and the highly potent nafamostat mesylate (21, K i 0.095 nM) [140] that are used clinically for the treatment of pancreatitis and as anticoagulants. The structurally best-characterized inhibitors among this group are the pyrazinone derivative 22 (K i 138 nM) [141] and the 4-(3-aminomethyl-phenyl)piperidinyl-1-amide 23 (K i 15 nM) [142]. The structure of 22 in complex with tryptase shows that the carbonyl oxygen of the pyrazinone forms an external hydrogen bond with Glu192 and, simultaneously, an internal hydrogen bond with the amide NH of the benzylamine moiety.…”

“…The Natom of the pyridine points away from the protein surface and the distance to the pyridine nitrogen of an inhibitor molecule interacting with the active site cleft of an neighbor- ing subunit is ~ 5.5 Å. A water molecule is located on the connecting line between these nitrogens, forming H-bonds with both of them [142]. Similarly, a preliminary X-ray crystallographic study of inhibitor 24 (K i 1.3 nM) in complex with tryptase has shown two inhibitor molecules interacting with the active sites of adjacent subunits that are connected to each other by bifurcated hydrogen bonds between their carboxamide groups [143].…”

Targeting Serine Proteases in Asthma

“…However, this inhibitor has disappeared from the R&D portfolio of the company (http://en.sanofi-aventis.com/rd/portfolio/p_rd_ portfolio_medecine_interne.asp; access date: 17 Jan 2006). The screening of in-house inhibitors of factor Xa, a serine protease closely related to tryptase, identified a β-amidoester as a lead to optimize tryptase inhibitors [61]. From an achiral piperidine derivative, acting as a surrogate of the initial template, they developed a completely new class of βII-tryptase inhibitors termed 4-(3-aminomethylphenyl) piperidinyl-1-amides [61].…”

“…The screening of in-house inhibitors of factor Xa, a serine protease closely related to tryptase, identified a β-amidoester as a lead to optimize tryptase inhibitors [61]. From an achiral piperidine derivative, acting as a surrogate of the initial template, they developed a completely new class of βII-tryptase inhibitors termed 4-(3-aminomethylphenyl) piperidinyl-1-amides [61]. By using an indole scaffold as a hydrophobic substituent on a m-benzylaminepiperidine template, the same group developed a new series of potent and selective inhibitors of tryptase [62].…”