Structure-based library design and the discovery of a potent and selective mast cell ß-tryptase inhibitor as an oral therapeutic agent.

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.

Predicting peak kinematic and kinetic parameters from gait speed.

OBJECTIVE: The aim of this study is to assess the predictability of the relationships between gait speed and common peak sagittal plane parameters in order to provide a set of reference parameter values. DESIGN: Lower extremity biomechanical data were collected in 64 healthy adults while walking barefoot at his/her comfortable walking speed, then at self-selected fast, slow and very slow speeds. Twenty seven peak joint parameter values were plotted and regressed as a function of gait speed. DISCUSSION: While most parameters change with increasing gait speed, in general, the kinetic parameters had better predictability than the kinematic parameters. Most of the power parameters were found to have a quadratic relationship with gait speed. Of the moment parameters, four had a linear relationship with gait speed, while four had a quadratic one. These relationships shown in the tables and graphs here can be used as a reference for 'normal' gait parameter values.

Virtual Screening and X-ray Crystallography for Human Kallikrein 6 Inhibitors with an Amidinothiophene P1 Group.

A series of compounds with an amidinothiophene P1 group and a pyrrolidinone-sulphonamide scaffold linker was identified as potent inhibitors of human kallikrein 6 by structure-based virtual screening based on the union accessible binding space of serine proteases. As the first series of potent nonmechanism-based hK6 inhibitors, they may be used as tool compounds for target validation. An X-ray structure of a representative compound complexed with hK6, resolved at a resolution of 1.88 Å, revealed that the amidinothiophene moiety bound in the S1 pocket and the pyrrolidinone-sulphonamide linker projected the aromatic tail into the S' pocket.

Synthesis and SAR of novel 4,5-diarylimidazolines as potent P2X7 receptor antagonists.

A series of 4,5-diarylimidazoline libraries were prepared using high-throughput solid-phase and microwave techniques. The compounds were evaluated as P2X(7) antagonists and their SAR is described.

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

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.