A Novel, Potent Dual Inhibitor of the Leukocyte Proteases Cathepsin G and Chymase

Garavilla, Lawrence de; Greco, Michael N.; Sukumar, N.; Chen, Zhiwei; Pineda, Agustin O.; Mathews, F.S.; Di, Enrico; Giardino, Edward C.; Wells, Grace I.; Haertlein, Barbara J.; Kauffman, Jack A.; Corcoran, Thomas W.; Derian, Claudia K.; Eckardt, Annette J.; Damiano, Bruce P.; Andrade‐Gordon, Patricia; Maryanoff, Bruce E.

doi:10.1074/jbc.m501302200

Cited by 89 publications

(89 citation statements)

References 44 publications

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“…parasite significantly diminished infection in cell culture, emphasizing the potential of this family of enzymes as a drug target 1 . A dual-active inhibitor of leukocyte protease cathepsin G and mast cell chymase has been proposed as a drug candidate for the simultaneous treatment of asthma and chronic obstructive pulmonary disease 2 . One of the selective human mast cell chymase inhibitors was active as an anti-inflammatory agent in several animal models of inflammation 3 .…”

Section: Introductionmentioning

confidence: 99%

Novel diphenyl esters of peptidyl α-aminoalkylphosphonates as inhibitors of chymotrypsin and subtilisin

Pietrusewicz

Sieńczyk

Oleksyszyn

2009

Journal of Enzyme Inhibition and Medicinal Chemistry

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Section: Introductionmentioning

confidence: 99%

Novel diphenyl esters of peptidyl α-aminoalkylphosphonates as inhibitors of chymotrypsin and subtilisin

Pietrusewicz

Sieńczyk

Oleksyszyn

2009

Journal of Enzyme Inhibition and Medicinal Chemistry

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“…CatG may play a role in the pathogenesis of various inflammatory diseases (11,28,41), and catG inhibitors were suggested to have potential for treating asthma, psoriasis, and rheumatoid arthritis (11,21), for which frankincense extracts were proposed to have therapeutic benefit (1,2). Nevertheless, experiments with catG-deficient mice led to controversial results regarding the importance of catG in chemoinvasion and in inflammatory processes.…”

Section: Discussionmentioning

confidence: 98%

“…Comparisons of pharmacological actions of BAs and of JNJ-10311795 in vivo reported in the literature indicate that the substances exhibit related properties. Thus, JNJ-10311795 efficiently inhibited glycogen-induced rat peritonitis and blocked LPS-induced rat airway neutrophilia (28). Similarly, mixtures of BAs or frankincense extracts impaired carrageenan-induced pleurisy in rats accompanied by reduced neutrophil infiltration (40).…”

Section: Discussionmentioning

confidence: 99%

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Identification of Human Cathepsin G As a Functional Target of Boswellic Acids from the Anti-Inflammatory Remedy Frankincense

Tausch

Henkel

Siemoneit

et al. 2009

The Journal of Immunology

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Frankincense preparations, used in folk medicine to cure inflammatory diseases, showed anti-inflammatory effectiveness in animal models and clinical trials. Boswellic acids (BAs) constitute major pharmacological principles of frankincense, but their targets and the underlying molecular modes of action are still unclear. Using a BA-affinity Sepharose matrix, a 26-kDa protein was selectively precipitated from human neutrophils and identified as the lysosomal protease cathepsin G (catG) by mass spectrometry (MALDI-TOF) and by immunological analysis. In rigid automated molecular docking experiments BAs tightly bound to the active center of catG, occupying the same part of the binding site as the synthetic catG inhibitor JNJ-10311795 (2-[3-{methyl[1-(2-naphthoyl)piperidin-4-yl]amino}carbonyl)-2-naphthyl]-1-(1-naphthyl)-2-oxoethylphosphonic acid). BAs potently suppressed the proteolytic activity of catG (IC50 of ∼600 nM) in a competitive and reversible manner. Related serine proteases were significantly less sensitive against BAs (leukocyte elastase, chymotrypsin, proteinase-3) or not affected (tryptase, chymase). BAs inhibited chemoinvasion but not chemotaxis of challenged neutrophils, and they suppressed Ca2+ mobilization in human platelets induced by isolated catG or by catG released from activated neutrophils. Finally, oral administration of defined frankincense extracts significantly reduced catG activities in human blood ex vivo vs placebo. In conclusion, we show that catG is a functional and pharmacologically relevant target of BAs, and interference with catG could explain some of the anti-inflammatory properties of frankincense.

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“…For example, aromatic β-ketophosphonates have been shown to be potent β-lactamase inhibitors [1], dual inhibitor of human neutrophil Cat G and human mast cell chymase [2], but in the acid form the compounds have been proposed as a novel class of serine protease inhibitors [3]. The synthesis of β-ketophosphonates is the reaction of trialkyl phosphites and β-halogenoketones, but this method requires highly reactive β-halogenoketones [4].…”

Section: Introductionmentioning

confidence: 99%

Synthesis of Pyridyl- β -ketophosphonates

Wieszczycka¹,

Bukowski²,

Framski³

2017

MOCR

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Abstract. In this paper we report a three-stage synthesis of alkyl ethyl 2-oxo-2-(pyridin-2-, -3-and -4-yl)ethylphosphonates (2a-e, 3a-e, 4a-e) starting from commercially-available triethyl phosphite. Triethyl phosphite was first transesterified with alcohols in the presence of sodium catalyst to give the alkyl diethyl phosphites (1b-e) in low to moderate yields. The Claisen condensation between 2-lithioalkylphosphonates and ethyl pyridine-2-,-3-and -4-carboxylate, followed by an Arbusov reaction with methyl iodide, gave the final products in moderate yields. The structures of the products were confirmed by 1H-NMR, 13C-NMR, and 31P-NMR. Estimation of the pharmacotherapeutic potential has been accomplished for synthesized compounds on the basis of Prediction of Activity Spectra for Substances (PASS). , and the reaction of phosphite with epoxysulfones [8] or with silyl enol ethers using a hypervalent iodine compound [9]. Cyclic β-ketophosphonates can also be prepared in good yields by the reaction of a dialkyl phosphite anion and α -nitro epoxides [10]. The present paper, reports a simple method for the synthesis of 2-oxo-2-(pyridin-2-, -3-and -4-yl)ethylphosphonates (2a-e, 3a-e and 4a-e) starting from triethyl phosphite. ResultsAs shown in Scheme 1, the alkyl ethyl 2-oxo-2-(pyridin-2-, -3-and -4-yl)ethylphosphonates (2a-e, 3a-e, 4a-e) can be prepared using a three-stage procedure starting from commercially-available triethyl phosphite. In the first stage, alkyl diethyl phosphites (1b-e) are prepared by reaction of alcohols (butan-1-ol, hexan-1-ol, octan-1-ol and 2-ethylhexan-1-ol) with triethyl phosphite in the presence of Na as catalyst [11]. Then, the Arbusov rearrangement of alkyl diethyl phosphites was used to prepare alkyl ethyl methylphosphonates [12]. According to this procedure ethyl pyridine-2-, -3-or-4-carboxylate is transformed into the corresponding β-ketophosphonate by treatment with 1.2 equivalents of the lithium anion of diethyl methylphosphonate (11a) or alkyl ethyl methylphosphonate (11b-e) in THF at −78 ℃, in good yields. The results are shown in Table

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A Novel, Potent Dual Inhibitor of the Leukocyte Proteases Cathepsin G and Chymase

Cited by 89 publications

References 44 publications

Novel diphenyl esters of peptidyl α-aminoalkylphosphonates as inhibitors of chymotrypsin and subtilisin

Novel diphenyl esters of peptidyl α-aminoalkylphosphonates as inhibitors of chymotrypsin and subtilisin

Identification of Human Cathepsin G As a Functional Target of Boswellic Acids from the Anti-Inflammatory Remedy Frankincense

Synthesis of Pyridyl- β -ketophosphonates

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