Biochemical and Pharmacological Characterization of 2-(9-(2-Piperidinoethoxy)-4-oxo-4H-pyrido[1,2-a]pyrimidin-2-yloxymethyl)-4-(1-methylethyl)-6-methoxy-1,2-benzisothiazol-3(2H)-one-1,1-dioxide (SSR69071), a Novel, Orally Active Elastase Inhibitor

Kapui, Zoltán; Varga, Márton; Urban-Szabo, Katalin; Mikus, Endre G.; Szabó, Tibor; Szeredi, Judit; Bátori, Sándor; Finance, Olivier; Arányi, Péter

doi:10.1124/jpet.102.044263

Cited by 37 publications

(31 citation statements)

References 36 publications

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“…3A, Lane 3) and generated four major fragments with molecular weights similar to fragments generated by PMN cell proteases. The highly selective neutrophil elastase inhibitor SSR69071 [27] largely inhibited decorin degradation by PMN proteases (reduced by 92%, Lanes 1 and 2 in Fig. 3A and Fig.…”

Section: Resultsmentioning

confidence: 94%

Solar Ultraviolet Irradiation Induces Decorin Degradation in Human Skin Likely via Neutrophil Elastase

Xia

Liu

et al. 2013

PLoS ONE

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Exposure of human skin to solar ultraviolet (UV) irradiation induces matrix metalloproteinase-1 (MMP-1) activity, which degrades type I collagen fibrils. Type I collagen is the most abundant protein in skin and constitutes the majority of skin connective tissue (dermis). Degradation of collagen fibrils impairs the structure and function of skin that characterize skin aging. Decorin is the predominant proteoglycan in human dermis. In model systems, decorin binds to and protects type I collagen fibrils from proteolytic degradation by enzymes such as MMP-1. Little is known regarding alterations of decorin in response to UV irradiation. We found that solar-simulated UV irradiation of human skin in vivo stimulated substantial decorin degradation, with kinetics similar to infiltration of polymorphonuclear (PMN) cells. Proteases that were released from isolated PMN cells degraded decorin in vitro. A highly selective inhibitor of neutrophil elastase blocked decorin breakdown by proteases released from PMN cells. Furthermore, purified neutrophil elastase cleaved decorin in vitro and generated fragments with similar molecular weights as those resulting from protease activity released from PMN cells, and as observed in UV-irradiated human skin. Cleavage of decorin by neutrophil elastase significantly augmented fragmentation of type I collagen fibrils by MMP-1. Taken together, these data indicate that PMN cell proteases, especially neutrophil elastase, degrade decorin, and this degradation renders collagen fibrils more susceptible to MMP-1 cleavage. These data identify decorin degradation and neutrophil elastase as potential therapeutic targets for mitigating sun exposure-induced collagen fibril degradation in human skin.

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Section: Resultsmentioning

confidence: 94%

Solar Ultraviolet Irradiation Induces Decorin Degradation in Human Skin Likely via Neutrophil Elastase

Xia

Liu

et al. 2013

PLoS ONE

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“…Anal. calcd for C 24 H 15 N 5 O 2 S: C 65.89, H 3.46, N 16.01; found C 65.94, H 3.51, N 16.06. 6-(2-Fluorophenyl)-9-phenylamino-5H-thiazolo [3',2':2, 3]pyrido [4,5-d] 9,158.5,157.7,153.5,151.3,150.0,147.4,141.2,135.6,135.2,131.3,130.6,130.1,129.3,125.0,123.3,121.0,118.3,118.2,117.6,116.1,103.2;IR (KBr) ν max : 3342 (N-H), 1685 (C＝O) cm -1 . Anal.…”

Section: Synthesis Of 2-mentioning

confidence: 99%

“…[7] For example, this structural pattern is present in the known antiallergic agent ramastine [8] and human leukocyte elastase inhibitor SSR69071. [9] Therefore, search for new biologically active compounds in this series seems to be quite promising. Owing to these remarkably broad pharmacological properties, a variety of synthetic methods have been reported for the preparation of pyrido[1,2-a]pyrimidinone derivatives.…”

Section: Introductionmentioning

confidence: 99%

Iodine-Dimethyl sulfoxide Promoted Synthesis of Novel TetracyclicThiazolo[3',2':2,3]pyrido[4,5-d]pyrido[1,2-a]pyrimidinones

Xu¹,

Zhang²,

Zhang³

et al. 2019

Chinese Journal of Organic Chemistry

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An iodine-dimethyl sulfoxide (I 2-DMSO) promoted efficient method is described for the synthesis of thiazolo-[3',2':2,3]pyrido[4,5-d]pyrido[1,2-a]pyrimidin-5-ones (5) via Pictet-Spengler cyclization. The key intermediate, 2-(3-amino-5-phenylaminothiazolo-2-yl)-4H-pyrido[1,2-a]pyrimidin-4-one (3), was readily prepared from 2-chloromethyl-4H-pyrido-[1,2-a]pyrimidin-4-one (1) and potassium N-phenyl-N'-cyano-imido-thiocarbonate (2) by Thorpe-Ziegler isomerization. The novel synthetic method offers the advantage of mild reaction conditions, operational simplicity and higher yields.

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“…Based on the identification of cleavage fragment a, we speculated that neutrophil elastase contributed to ␣1-ACT fragmentation in chronic human wounds (valine at position P1 and alanine at position P3). To test this hypothesis, we analyzed the ability of SSR 69071, a potent inhibitor of human neutrophil elastase (IC 50 ϭ 3.9 nmol/liter) (34), to block r␣1-ACT fragmentation in wound exudate. Exudates characterized by high r␣1-ACT degrading and inactivating activity were incubated with SSR 69071 at different concentrations prior to addition of r␣1-ACT and for different times as indicated.…”

Section: Neutrophil Elastase Inhibitor Significantly Increases Stabilmentioning

confidence: 99%

Pivotal Role for α1-Antichymotrypsin in Skin Repair

Hoffmann

Textoris

Oehme

et al. 2011

Journal of Biological Chemistry

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α1-Antichymotrypsin (α1-ACT) is a specific inhibitor of leukocyte-derived chymotrypsin-like proteases with largely unknown functions in tissue repair. By examining human and murine skin wounds, we showed that following mechanical injury the physiological repair response is associated with an acute phase response of α1-ACT and the mouse homologue Spi-2, respectively. In both species, attenuated α1-ACT/Spi-2 activity and gene expression at the local wound site was associated with severe wound healing defects. Topical application of recombinant α1-ACT to wounds of diabetic mice rescued the impaired healing phenotype. LC-MS analysis of α1-ACT cleavage fragments identified a novel cleavage site within the reactive center loop and showed that neutrophil elastase was the predominant protease involved in unusual α1-ACT cleavage and inactivation in nonhealing human wounds. These results reveal critical functions for locally acting α1-ACT in the acute phase response following skin injury, provide mechanistic insight into its function during the repair response, and raise novel perspectives for its potential therapeutic value in inflammation-mediated tissue damage.

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Biochemical and Pharmacological Characterization of 2-(9-(2-Piperidinoethoxy)-4-oxo-4H-pyrido[1,2-a]pyrimidin-2-yloxymethyl)-4-(1-methylethyl)-6-methoxy-1,2-benzisothiazol-3(2H)-one-1,1-dioxide (SSR69071), a Novel, Orally Active Elastase Inhibitor

Cited by 37 publications

References 36 publications

Solar Ultraviolet Irradiation Induces Decorin Degradation in Human Skin Likely via Neutrophil Elastase

Solar Ultraviolet Irradiation Induces Decorin Degradation in Human Skin Likely via Neutrophil Elastase

Iodine-Dimethyl sulfoxide Promoted Synthesis of Novel TetracyclicThiazolo[3',2':2,3]pyrido[4,5-d]pyrido[1,2-a]pyrimidinones

Pivotal Role for α1-Antichymotrypsin in Skin Repair

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