title: Potent, small-molecule inhibitors of human mast cell tryptase. Antiasthmatic action of a dipeptide-based transition-state analogue containing a benzothiazole ketone.
abstract: Inhibitors of human mast cell tryptase (EC 3.4.21.59) have therapeutic potential for treating allergic or inflammatory disorders. We have investigated transition-state mimetics possessing a heterocycle-activated ketone group and identified in particular benzothiazole ketone (2S)-6 (RWJ-56423) as a potent, reversible, low-molecular-weight tryptase inhibitor with a K(i) value of 10 nM. A single-crystal X-ray analysis of the sulfate salt of (2S)-6 confirmed the stereochemistry. Analogues 12 and 15-17 are also potent tryptase inhibitors. Although RWJ-56423 potently inhibits trypsin (K(i) = 8.1 nM), it is selective vs other serine proteases, such as kallikrein, plasmin, and thrombin. We obtained an X-ray structure of (2S)-6 complexed with bovine trypsin (1.9-A resolution), which depicts inter alia a hemiketal involving Ser-189, and hydrogen bonds with His-57 and Gln-192. Aerosol administration of 6 (2R,2S; RWJ-58643) to allergic sheep effectively antagonized antigen-induced asthmatic responses, with 70-75% blockade of the early response and complete ablation of the late response and airway hyperresponsiveness.
authors.affiliation: Drug Discovery, Johnson & Johnson Pharmaceutical Research & Development, Spring House, Pennsylvania 19477-0776, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Costanzo
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Yabut
authors.forename: Harold R
authors.initials: HR
authors.lastname: Almond
authors.forename: Patricia
authors.initials: P
authors.lastname: Andrade-Gordon
authors.forename: Thomas W
authors.initials: TW
authors.lastname: Corcoran
authors.forename: Lawrence
authors.initials: L
authors.lastname: De Garavilla
authors.forename: Jack A
authors.initials: JA
authors.lastname: Kauffman
authors.forename: William M
authors.initials: WM
authors.lastname: Abraham
authors.forename: Rosario
authors.initials: R
authors.lastname: Recacha
authors.forename: Debashish
authors.initials: D
authors.lastname: Chattopadhyay
authors.forename: Bruce E
authors.initials: BE
authors.lastname: Maryanoff
mesh_terms: D000336:Aerosols; D000818:Animals; D018927:Anti-Asthmatic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001249:Asthma / Q000188:drug therapy / Q000276:immunology / Q000503:physiopathology; D052160:Benzothiazoles; D002417:Cattle; D018360:Crystallography, X-Ray; D004151:Dipeptides / Q000737:chemistry*; D006801:Humans; D007659:Ketones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007700:Kinetics; D008407:Mast Cells / Q000201:enzymology; D008958:Models, Molecular; D011485:Protein Binding; D011759:Pyrrolidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D012697:Serine Endopeptidases / Q000378:metabolism*; D015842:Serine Proteinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D012756:Sheep; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014357:Trypsin / Q000737:chemistry; D053802:Tryptases
chemical_list: C477196:1-acetyl-N-(4-((aminoiminomethyl)amino)-1-(2-benzothiazolylcarbonyl)butyl)-4-hydroxy-2-pyrrolidinecarboxamide; D000336:Aerosols; D018927:Anti-Asthmatic Agents; D052160:Benzothiazoles; D004151:Dipeptides; D007659:Ketones; D011759:Pyrrolidines; D015842:Serine Proteinase Inhibitors; D013844:Thiazoles; D012697:Serine Endopeptidases; D014357:Trypsin; D053802:Tryptases