Download MendeleyPotent, nonpeptide inhibitors of human mast cell tryptase. Synthesis and biological evaluation of novel spirocyclic piperidine amide derivatives
Costanzo, M.J., Yabut, S.C., Zhang, H.-C., White, K.B., de Garavilla, L., Wang, Y., Minor, L.K., Tounge, B.A., Barnakov, A.N., Lewandowski, F., Milligan, C., Spurlino, J.C., Abraham, W.M., Boswell-Smith, V., Page, C.P., Maryanoff, B.E.(2008) Bioorg Med Chem Lett 18: 2114-2121
- PubMed: 18272363
- DOI: https://doi.org/10.1016/j.bmcl.2008.01.093
- Primary Citation of Related Structures:
2ZA5, 2ZEB, 2ZEC - 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.
Organizational Affiliation:
Research and Early Development, Johnson & Johnson Pharmaceutical Research & Development, Welsh & McKean Roads, Spring House, PA 19477-0776, USA. [email protected]
