Article

Potent, nonpeptide inhibitors of human mast cell tryptase. Synthesis and biological evaluation of novel spirocyclic piperidine amide derivatives.

Research and Early Development, Johnson & Johnson Pharmaceutical Research & Development, Welsh & McKean Roads, Spring House, PA 19477-0776, USA.
Bioorganic & medicinal chemistry letters (impact factor: 2.65). 04/2008; 18(6):2114-21. DOI:10.1016/j.bmcl.2008.01.093 pp.2114-21
Source: PubMed

ABSTRACT We have explored a series of spirocyclic piperidine amide derivatives (5) as tryptase inhibitors. Thus, 4 (JNJ-27390467) was identified as a potent, selective tryptase inhibitor with oral efficacy in two animal models of airway inflammation (sheep and guinea pig asthma models). An X-ray co-crystal structure of 4 x tryptase revealed a hydrophobic pocket in the enzyme's active site, which is induced by the phenylethynyl group and is comprised of amino acid residues from two different monomers of the tetrameric protein.

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Keywords

4 x tryptase
 
airway inflammation
 
amino acid residues
 
animal models
 
enzyme's active site
 
oral efficacy
 
spirocyclic piperidine amide derivatives
 
tetrameric protein
 
X-ray co-crystal structure