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1.
Bioorg Med Chem Lett ; 22(9): 3370-6, 2012 May 01.
Article in English | MEDLINE | ID: mdl-22483389

ABSTRACT

The tetrameric folding of ß-tryptase and the pair-wise distribution of its substrate binding sites offer a unique opportunity for development of inhibitors that span two adjacent binding sites. A series of dimeric inhibitors with two basic P1 moieties was discovered using this design strategy and exhibited tight-binder characteristics. Using the same strategy, an attempt was made to design and synthesize dimeric inhibitors with two neutral-P1 groups in hope to exploit the dimeric binding mode to achieve a starting point for further optimization. The unsuccessful attempt, however, demonstrated the important role played by Ala190 in neutral-P1 binding and casted further doubt on the possibility of developing neutral-P1 inhibitors for ß-tryptase.


Subject(s)
Protein Multimerization/drug effects , Serine Proteinase Inhibitors/chemistry , Serine Proteinase Inhibitors/pharmacology , Tryptases/antagonists & inhibitors , Binding Sites
2.
Bioorg Med Chem Lett ; 22(4): 1606-10, 2012 Feb 15.
Article in English | MEDLINE | ID: mdl-22264487

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/pharmacology
3.
Bioorg Med Chem Lett ; 22(2): 1049-54, 2012 Jan 15.
Article in English | MEDLINE | ID: mdl-22192588

ABSTRACT

A solid phase combinatorial library was designed based on X-ray structures and in-silico models to explore an inducible S4+ pocket, which is formed by a simple side-chain rotation of Tyr95. This inducible S4+ pocket is unique to ß-tryptase and does not exist for other trypsin-like serine proteases of interest. Therefore, inhibitors utilizing this pocket have inherent advantages for being selective against other proteases in the same family. A member of this library was found to be a potent and selective ß-tryptase inhibitor with a suitable pharmacokinetic profile for further clinical evaluation.


Subject(s)
Enzyme Inhibitors/pharmacology , Mast Cells/enzymology , Small Molecule Libraries/pharmacology , Tryptases/antagonists & inhibitors , Administration, Oral , Animals , Combinatorial Chemistry Techniques , Crystallography, X-Ray , Dose-Response Relationship, Drug , Enzyme Inhibitors/administration & dosage , Enzyme Inhibitors/chemical synthesis , Humans , Models, Molecular , Molecular Structure , Rats , Recombinant Proteins/antagonists & inhibitors , Small Molecule Libraries/administration & dosage , Small Molecule Libraries/chemical synthesis , Structure-Activity Relationship
4.
Bioorg Med Chem Lett ; 20(22): 6721-4, 2010 Nov 15.
Article in English | MEDLINE | ID: mdl-20855210

ABSTRACT

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 Diffraction
5.
Bioorg Med Chem Lett ; 20(6): 1981-4, 2010 Mar 15.
Article in English | MEDLINE | ID: mdl-20153645

ABSTRACT

Amino-benzoic acid derivatives 1-4 were found to be inhibitors for DHODH by virtual screening, biochemical, and X-ray crystallographic studies. X-ray structures showed that 1 and 2 bind to DHODH as predicted by virtual screening, but 3 and 4 were found to be structurally different from the corresponding compounds initially identified by virtual screening.


Subject(s)
Enzyme Inhibitors/chemistry , Oxidoreductases Acting on CH-CH Group Donors/antagonists & inhibitors , Crystallography, X-Ray , Dihydroorotate Dehydrogenase , Drug Discovery , Enzyme Inhibitors/pharmacology , Models, Molecular , Molecular Structure
7.
Bioorg Med Chem ; 13(8): 2859-72, 2005 Apr 15.
Article in English | MEDLINE | ID: mdl-15781396

ABSTRACT

Tryptase is a serine protease found almost exclusively in mast cells. It has trypsin-like specificity, favoring cleavage of substrates with an arginine (or lysine) at the P1 position, and has optimal catalytic activity at neutral pH. Current evidence suggests tryptase beta is the most important form released during mast cell activation in allergic diseases. It is shown to have numerous pro-inflammatory cellular activities in vitro, and in animal models tryptase provokes broncho-constriction and induces a cellular inflammatory infiltrate characteristic of human asthma. Screening of in-house inhibitors of factor Xa (a closely related serine protease) identified beta-amidoester benzamidines as potent inhibitors of recombinant human betaII tryptase. X-ray structure driven template modification and exchange of the benzamidine to optimize potency and pharmacokinetic properties gave selective, potent and orally bioavailable 4-(3-aminomethyl phenyl)piperidinyl-1-amides.


Subject(s)
Amides , Piperidines , Serine Endopeptidases/drug effects , Administration, Oral , Amides/chemical synthesis , Amides/chemistry , Amides/pharmacology , Animals , Biological Availability , Caco-2 Cells , Crystallography, X-Ray , Drug Design , Factor Xa Inhibitors , Humans , Liver/enzymology , Models, Molecular , Molecular Structure , Piperidines/chemical synthesis , Piperidines/chemistry , Piperidines/pharmacology , Protein Conformation , Rats , Recombinant Proteins/drug effects , Serine Proteinase Inhibitors/chemical synthesis , Serine Proteinase Inhibitors/chemistry , Serine Proteinase Inhibitors/pharmacology , Structure-Activity Relationship , Tryptases
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