Potent, small-molecule inhibitors of human mast cell tryptase. Antiasthmatic action of a dipeptide-based transition-state analogue containing a benzothiazole ketone

Michael J Costanzo; Stephen C Yabut; Harold R Almond Jr; Patricia Andrade-Gordon; Thomas W Corcoran; Lawrence De Garavilla; Jack A Kauffman; William M Abraham; Rosario Recacha; Debashish Chattopadhyay; Bruce E Maryanoff

doi:10.1021/jm030050p

Potent, small-molecule inhibitors of human mast cell tryptase. Antiasthmatic action of a dipeptide-based transition-state analogue containing a benzothiazole ketone

J Med Chem. 2003 Aug 28;46(18):3865-76. doi: 10.1021/jm030050p.

Authors

Michael J Costanzo¹, Stephen C Yabut, Harold R Almond Jr, Patricia Andrade-Gordon, Thomas W Corcoran, Lawrence De Garavilla, Jack A Kauffman, William M Abraham, Rosario Recacha, Debashish Chattopadhyay, Bruce E Maryanoff

Affiliation

¹ Drug Discovery, Johnson & Johnson Pharmaceutical Research & Development, Spring House, Pennsylvania 19477-0776, USA.

PMID: 12930148
DOI: 10.1021/jm030050p

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.

MeSH terms

Aerosols
Animals
Anti-Asthmatic Agents / chemical synthesis*
Anti-Asthmatic Agents / chemistry
Anti-Asthmatic Agents / pharmacology
Asthma / drug therapy
Asthma / immunology
Asthma / physiopathology
Benzothiazoles
Cattle
Crystallography, X-Ray
Dipeptides / chemistry*
Humans
Ketones / chemical synthesis*
Ketones / chemistry
Ketones / pharmacology
Kinetics
Mast Cells / enzymology
Models, Molecular
Protein Binding
Pyrrolidines / chemical synthesis*
Pyrrolidines / chemistry
Pyrrolidines / pharmacology
Serine Endopeptidases / metabolism*
Serine Proteinase Inhibitors / chemical synthesis*
Serine Proteinase Inhibitors / chemistry
Serine Proteinase Inhibitors / pharmacology
Sheep
Stereoisomerism
Structure-Activity Relationship
Thiazoles / chemical synthesis*
Thiazoles / chemistry
Thiazoles / pharmacology
Trypsin / chemistry
Tryptases

Substances

1-acetyl-N-(4-((aminoiminomethyl)amino)-1-(2-benzothiazolylcarbonyl)butyl)-4-hydroxy-2-pyrrolidinecarboxamide
Aerosols
Anti-Asthmatic Agents
Benzothiazoles
Dipeptides
Ketones
Pyrrolidines
Serine Proteinase Inhibitors
Thiazoles
Serine Endopeptidases
Trypsin
Tryptases