title: Potent, nonpeptide inhibitors of human mast cell tryptase. Synthesis and biological evaluation of novel spirocyclic piperidine amide derivatives.
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.
authors.affiliation: Research and Early Development, Johnson & Johnson Pharmaceutical Research & Development, Welsh & McKean Roads, Spring House, PA 19477-0776, USA. mcostanz@prdus.jnj.com
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Costanzo
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Yabut
authors.forename: Han-Cheng
authors.initials: HC
authors.lastname: Zhang
authors.forename: Kimberley B
authors.initials: KB
authors.lastname: White
authors.forename: Lawrence
authors.initials: L
authors.lastname: de Garavilla
authors.forename: Yuanping
authors.initials: Y
authors.lastname: Wang
authors.forename: Lisa K
authors.initials: LK
authors.lastname: Minor
authors.forename: Brett A
authors.initials: BA
authors.lastname: Tounge
authors.forename: Alexander N
authors.initials: AN
authors.lastname: Barnakov
authors.forename: Frank
authors.initials: F
authors.lastname: Lewandowski
authors.forename: Cynthia
authors.initials: C
authors.lastname: Milligan
authors.forename: John C
authors.initials: JC
authors.lastname: Spurlino
authors.forename: William M
authors.initials: WM
authors.lastname: Abraham
authors.forename: Victoria
authors.initials: V
authors.lastname: Boswell-Smith
authors.forename: Clive P
authors.initials: CP
authors.lastname: Page
authors.forename: Bruce E
authors.initials: BE
authors.lastname: Maryanoff
mesh_terms: 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
chemical_list: D065607:Cytochrome P-450 Enzyme Inhibitors; C529339:JNJ-27390467; D015842:Serine Proteinase Inhibitors; D013141:Spiro Compounds; D014357:Trypsin; D053802:Tryptases