Potent, nonpeptide inhibitors of human mast cell tryptase. Synthesis and biological evaluation of novel spirocyclic piperidine amide derivatives.
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.
Costanzo
Michael J
MJ
Research and Early Development, Johnson & Johnson Pharmaceutical Research & Development, Welsh & McKean Roads, Spring House, PA 19477-0776, USA. mcostanz@prdus.jnj.com
Yabut
Stephen C
SC
Zhang
Han-Cheng
HC
White
Kimberley B
KB
de Garavilla
Lawrence
L
Wang
Yuanping
Y
Minor
Lisa K
LK
Tounge
Brett A
BA
Barnakov
Alexander N
AN
Lewandowski
Frank
F
Milligan
Cynthia
C
Spurlino
John C
JC
Abraham
William M
WM
Boswell-Smith
Victoria
V
Page
Clive P
CP
Maryanoff
Bruce E
BE
D000284:Administration, Oral; D000818:Animals; D001249:Asthma / Q000188:drug therapy*; D001682:Biological Availability; D002851:Chromatography, High Pressure Liquid; D018360:Crystallography, X-Ray; D065607:Cytochrome P-450 Enzyme Inhibitors; D004195:Disease Models, Animal; D004285:Dogs; D006168:Guinea Pigs; D006801:Humans; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D015394:Molecular Structure; D051381:Rats; D012130:Respiratory Hypersensitivity / Q000188:drug therapy*; D015842:Serine Proteinase Inhibitors / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D012756:Sheep; D021241:Spectrometry, Mass, Electrospray Ionization; D013141:Spiro Compounds / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D014357:Trypsin / Q000378:metabolism; D053802:Tryptases / Q000037:antagonists & inhibitors* / Q000378:metabolism
D065607:Cytochrome P-450 Enzyme Inhibitors; C529339:JNJ-27390467; D015842:Serine Proteinase Inhibitors; D013141:Spiro Compounds; D014357:Trypsin; D053802:Tryptases