|
Inhibition of TACE
|
Homo sapiens
|
20.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Acetylenic TACE inhibitors. Part 3: Thiomorpholine sulfonamide hydroxamates.
Year : 2006
Volume : 16
Issue : 6
First Page : 1605
Last Page : 1609
Authors : Levin JI, Chen JM, Laakso LM, Du M, Schmid J, Xu W, Cummons T, Xu J, Jin G, Barone D, Skotnicki JS.
Abstract : A series of thiomorpholine sulfonamide hydroxamate TACE inhibitors, all bearing propargylic ether P1' groups, was explored. In particular, compound 5h has excellent in vitro potency against isolated TACE enzyme and in cells, oral activity in a model of TNF-alpha production and a collagen-induced arthritis model, was selected as a clinical candidate for the treatment of RA.
|
Inhibition of MMP1
|
Homo sapiens
|
33.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Acetylenic TACE inhibitors. Part 3: Thiomorpholine sulfonamide hydroxamates.
Year : 2006
Volume : 16
Issue : 6
First Page : 1605
Last Page : 1609
Authors : Levin JI, Chen JM, Laakso LM, Du M, Schmid J, Xu W, Cummons T, Xu J, Jin G, Barone D, Skotnicki JS.
Abstract : A series of thiomorpholine sulfonamide hydroxamate TACE inhibitors, all bearing propargylic ether P1' groups, was explored. In particular, compound 5h has excellent in vitro potency against isolated TACE enzyme and in cells, oral activity in a model of TNF-alpha production and a collagen-induced arthritis model, was selected as a clinical candidate for the treatment of RA.
|
Inhibition of MMP13
|
Homo sapiens
|
8.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Acetylenic TACE inhibitors. Part 3: Thiomorpholine sulfonamide hydroxamates.
Year : 2006
Volume : 16
Issue : 6
First Page : 1605
Last Page : 1609
Authors : Levin JI, Chen JM, Laakso LM, Du M, Schmid J, Xu W, Cummons T, Xu J, Jin G, Barone D, Skotnicki JS.
Abstract : A series of thiomorpholine sulfonamide hydroxamate TACE inhibitors, all bearing propargylic ether P1' groups, was explored. In particular, compound 5h has excellent in vitro potency against isolated TACE enzyme and in cells, oral activity in a model of TNF-alpha production and a collagen-induced arthritis model, was selected as a clinical candidate for the treatment of RA.
|
Inhibition of LPS-stimulated TNF production in THP cells at 3 uM
|
Homo sapiens
|
95.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Acetylenic TACE inhibitors. Part 3: Thiomorpholine sulfonamide hydroxamates.
Year : 2006
Volume : 16
Issue : 6
First Page : 1605
Last Page : 1609
Authors : Levin JI, Chen JM, Laakso LM, Du M, Schmid J, Xu W, Cummons T, Xu J, Jin G, Barone D, Skotnicki JS.
Abstract : A series of thiomorpholine sulfonamide hydroxamate TACE inhibitors, all bearing propargylic ether P1' groups, was explored. In particular, compound 5h has excellent in vitro potency against isolated TACE enzyme and in cells, oral activity in a model of TNF-alpha production and a collagen-induced arthritis model, was selected as a clinical candidate for the treatment of RA.
|
Inhibition of LPS-stimulated TNF production in THP cells at 1 uM
|
Homo sapiens
|
89.0
%
|
|
Inhibition of LPS-stimulated TNF production in THP cells at 1 uM
|
Homo sapiens
|
140.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Acetylenic TACE inhibitors. Part 3: Thiomorpholine sulfonamide hydroxamates.
Year : 2006
Volume : 16
Issue : 6
First Page : 1605
Last Page : 1609
Authors : Levin JI, Chen JM, Laakso LM, Du M, Schmid J, Xu W, Cummons T, Xu J, Jin G, Barone D, Skotnicki JS.
Abstract : A series of thiomorpholine sulfonamide hydroxamate TACE inhibitors, all bearing propargylic ether P1' groups, was explored. In particular, compound 5h has excellent in vitro potency against isolated TACE enzyme and in cells, oral activity in a model of TNF-alpha production and a collagen-induced arthritis model, was selected as a clinical candidate for the treatment of RA.
|
Inhibition of LPS-stimulated TNFalpha production in mouse at 50 mg/kg, po
|
Mus musculus
|
95.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Acetylenic TACE inhibitors. Part 3: Thiomorpholine sulfonamide hydroxamates.
Year : 2006
Volume : 16
Issue : 6
First Page : 1605
Last Page : 1609
Authors : Levin JI, Chen JM, Laakso LM, Du M, Schmid J, Xu W, Cummons T, Xu J, Jin G, Barone D, Skotnicki JS.
Abstract : A series of thiomorpholine sulfonamide hydroxamate TACE inhibitors, all bearing propargylic ether P1' groups, was explored. In particular, compound 5h has excellent in vitro potency against isolated TACE enzyme and in cells, oral activity in a model of TNF-alpha production and a collagen-induced arthritis model, was selected as a clinical candidate for the treatment of RA.
|
Inhibition of TACE
|
None
|
440.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Current perspective of TACE inhibitors: a review.
Year : 2009
Volume : 17
Issue : 2
First Page : 444
Last Page : 459
Authors : DasGupta S, Murumkar PR, Giridhar R, Yadav MR.
Abstract : Rheumatoid Arthritis (RA) is one of the most common autoimmune inflammatory conditions, affecting approximately 1% of the adult population worldwide. TNF-alpha is a pleitropic, pro-inflammatory cytokine which plays a pivotal role in the origin and progression of RA and other immune mediated disorders. The success of anti-TNF-alpha biological agents proved that inhibition of TNF-alpha could result in effective control of RA. Since the discovery of anti-TNF-alpha biologicals, much efforts have gone into developing an orally bioavailable small size TNF-alpha antagonist. One of the ways to block TNF-alpha in biological fluids is to inhibit TNF-alpha converting enzyme (TACE). This target has been validated in preclinical trials using TACE inhibitors. But, even after more than a decade no single TACE inhibitor has passed the Phase II clinical trials. Very recently, it has been shown that TACE inhibitors could also be used for inhibition of pathogenic EGFR signaling in cancer. Hence, TACE inhibitors could perform a dual role, in curing not only RA but also certain cancerous conditions. Developments in the field have prompted us to review the research work on TACE inhibitors, especially their structure activity relationships and molecular modeling studies.
|
TACE Enzyme Assay: The TACE enzyme is an internal production (carried out according to the publication Protein Eng Des Sel, 2006, 19, 155-161) and is added so as to have a signal equivalent to 6 times the background noise over 2 h at 37° C. The reaction takes place in a buffered medium: Tris 50 mM, 4% of glycerol, pH 7.4. The fluorescent substrate is MCA-Pro-Leu-Ala-Val-(Dpa)-Arg-Ser-Ser-Arg-NH2 (R&D system reference: ES003). The substrate is cleaved by the enzyme between alanine and valine thus releasing a fluorescent peptide (excitation: 320 nm, emission: 420 nm). The substrate is used at 40 uM. The reaction is carried out in a final volume of 10 ul (4 ul inhibitor, 4 ul substrate, 2 ul enzyme) in a plate of 384 low-volume wells (Corning reference: 3676). The plate is incubated for 2 h at ambient temperature, then read in fluorescence mode using a Pherastar (BMG labtech).
|
None
|
5.0
nM
|
|
Title : 4-alkoxy-N-(2-hydroxycarbamoyl-2-piperidinyl-ethyl)-benzamide compounds as selective TACE-inhibitors for the treatment of inflammatory diseases
Year : 2016
|
Inhibition Assay: The molecules are tested in dose-response studies on the following enzymes MMP1, MMP3, MMP9, ADAM9 and ADAM10 according to the same protocol as that described for the TACE enzyme in example 28 but with different substrates (MMP R&D system reference: P126-990 and ADAM R&D system reference: ES003).
|
None
|
145.0
nM
|
|
Title : 4-alkoxy-N-(2-hydroxycarbamoyl-2-piperidinyl-ethyl)-benzamide compounds as selective TACE-inhibitors for the treatment of inflammatory diseases
Year : 2016
|
Inhibition Assay: The molecules are tested in dose-response studies on the following enzymes MMP1, MMP3, MMP9, ADAM9 and ADAM10 according to the same protocol as that described for the TACE enzyme in example 28 but with different substrates (MMP R&D system reference: P126-990 and ADAM R&D system reference: ES003).
|
None
|
10.0
nM
|
|
Title : 4-alkoxy-N-(2-hydroxycarbamoyl-2-piperidinyl-ethyl)-benzamide compounds as selective TACE-inhibitors for the treatment of inflammatory diseases
Year : 2016
|
Inhibition Assay: The molecules are tested in dose-response studies on the following enzymes MMP1, MMP3, MMP9, ADAM9 and ADAM10 according to the same protocol as that described for the TACE enzyme in example 28 but with different substrates (MMP R&D system reference: P126-990 and ADAM R&D system reference: ES003).
|
Homo sapiens
|
82.0
nM
|
|
Title : 4-alkoxy-N-(2-hydroxycarbamoyl-2-piperidinyl-ethyl)-benzamide compounds as selective TACE-inhibitors for the treatment of inflammatory diseases
Year : 2016
|
Inhibition Assay: The molecules are tested in dose-response studies on the following enzymes MMP1, MMP3, MMP9, ADAM9 and ADAM10 according to the same protocol as that described for the TACE enzyme in example 28 but with different substrates (MMP R&D system reference: P126-990 and ADAM R&D system reference: ES003).
|
None
|
85.0
nM
|
|
Title : 4-alkoxy-N-(2-hydroxycarbamoyl-2-piperidinyl-ethyl)-benzamide compounds as selective TACE-inhibitors for the treatment of inflammatory diseases
Year : 2016
|
Inhibition Assay: The molecules are tested in dose-response studies on the following enzymes MMP1, MMP3, MMP9, ADAM9 and ADAM10 according to the same protocol as that described for the TACE enzyme in example 28 but with different substrates (MMP R&D system reference: P126-990 and ADAM R&D system reference: ES003).
|
None
|
71.0
nM
|
|
Title : 4-alkoxy-N-(2-hydroxycarbamoyl-2-piperidinyl-ethyl)-benzamide compounds as selective TACE-inhibitors for the treatment of inflammatory diseases
Year : 2016
|
Inhibition Assay: The TACE enzyme is an internal production (carried out according to the publication protein Eng Des Sel 2006, 19, 155-161) and is added so as to have a signal equivalent to 6 times the background noise in 2 h at 37° C. The reaction is carried out in 50 mM Tris buffered medium containing 4% glycerol, pH 7.4. The fluorescent substrate is MCA-Pro-Leu-Ala-Val-(Dpa)-Arg-Ser-Ser-Arg-NH2 (R&D systems, reference: ES003). The substrate is cleaved by the enzyme between the alanine and the valine, thus releasing a fluorescent peptide (excitation: 320 nm, emission: 420 nm). The substrate is used at 40 uM. The reaction is carried out in a final volume of 10 ul (4 ul inhibitor, 4 ul substrate, 2 ul enzyme) in a low volume 384-well plate (Corning reference: 3676). The plate is incubated at ambient temperature for 2 h, and then read by fluorescence on a Pherastar reader (BMG labtech).
|
None
|
5.0
nM
|
|
Title : Benzenesulfonamide compounds, method for synthesizing same, and use thereof in medicine as well as in cosmetics
Year : 2016
|
Inhibition Assay: The molecules are dose-response tested on the following enzymes: MMP1, MMP3, MMP9, ADAM9 and ADAM10, according to the same protocol as that described for the TACE enzyme in example 28, but with different substrates (MMP R&D systems, reference: P126-990, and ADAM R&D systems, reference: ES003).
|
None
|
145.0
nM
|
|
Title : Benzenesulfonamide compounds, method for synthesizing same, and use thereof in medicine as well as in cosmetics
Year : 2016
|
Inhibition Assay: The molecules are dose-response tested on the following enzymes: MMP1, MMP3, MMP9, ADAM9 and ADAM10, according to the same protocol as that described for the TACE enzyme in example 28, but with different substrates (MMP R&D systems, reference: P126-990, and ADAM R&D systems, reference: ES003).
|
None
|
10.0
nM
|
|
Title : Benzenesulfonamide compounds, method for synthesizing same, and use thereof in medicine as well as in cosmetics
Year : 2016
|
Inhibition Assay: The molecules are dose-response tested on the following enzymes: MMP1, MMP3, MMP9, ADAM9 and ADAM10, according to the same protocol as that described for the TACE enzyme in example 28, but with different substrates (MMP R&D systems, reference: P126-990, and ADAM R&D systems, reference: ES003).
|
Homo sapiens
|
82.0
nM
|
|
Title : Benzenesulfonamide compounds, method for synthesizing same, and use thereof in medicine as well as in cosmetics
Year : 2016
|
Inhibition Assay: The molecules are dose-response tested on the following enzymes: MMP1, MMP3, MMP9, ADAM9 and ADAM10, according to the same protocol as that described for the TACE enzyme in example 28, but with different substrates (MMP R&D systems, reference: P126-990, and ADAM R&D systems, reference: ES003).
|
None
|
85.0
nM
|
|
Title : Benzenesulfonamide compounds, method for synthesizing same, and use thereof in medicine as well as in cosmetics
Year : 2016
|
Inhibition Assay: The molecules are dose-response tested on the following enzymes: MMP1, MMP3, MMP9, ADAM9 and ADAM10, according to the same protocol as that described for the TACE enzyme in example 28, but with different substrates (MMP R&D systems, reference: P126-990, and ADAM R&D systems, reference: ES003).
|
None
|
71.0
nM
|
|
Title : Benzenesulfonamide compounds, method for synthesizing same, and use thereof in medicine as well as in cosmetics
Year : 2016
|
Inhibition of recombinant human TACE catalytic domain using Mca-Pro-Leu-Ala-Gln-Ala-Val-Dpa-Arg-Ser-Ser-Ser-Arg-NH2 as substrate after 2 hrs by fluorescence assay
|
Homo sapiens
|
4.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Identification of novel TACE inhibitors compatible with topical application.
Year : 2017
Volume : 27
Issue : 8
First Page : 1848
Last Page : 1853
Authors : Ouvry G, Berton Y, Bhurruth-Alcor Y, Bonnary L, Bouix-Peter C, Bouquet K, Bourotte M, Chambon S, Comino C, Deprez B, Duvert D, Duvert G, Hacini-Rachinel F, Harris CS, Luzy AP, Mathieu A, Millois C, Pascau J, Pinto A, Polge G, Reitz A, Reversé K, Rosignoli C, Taquet N, Hennequin LF.
Abstract : Targeting the Tumor Necrosis Factor α signalling with antibodies has led to a revolution in the treatment of psoriasis. Locally inhibiting Tumor Necrosis Factor α Converting Enzyme (TACE or ADAM17) could potentially mimic those effects and help treat mild to moderate psoriasis, without the reported side effect of systemic TACE inhibitors. Efforts to identify new TACE inhibitors are presented here. Enzymatic SAR as well as ADME and physico-chemistry data are presented. This study culminated in the identification of potent enzymatic inhibitors. Suboptimal cellular activity of this series is discussed in the context of previously published results.
|
Inhibition of TACE in NHEK assessed as reduction in LPS/TPA-stimulated TNFalpha production preincubated for 1 hr followed by LPS/TPA stimulation for 24 hrs by HTRF assay
|
Homo sapiens
|
120.0
nM
|
|
Inhibition of TACE in NHEK assessed as reduction in LPS/TPA-stimulated TNFalpha production preincubated for 1 hr followed by LPS/TPA stimulation for 24 hrs by HTRF assay
|
Homo sapiens
|
125.89
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Identification of novel TACE inhibitors compatible with topical application.
Year : 2017
Volume : 27
Issue : 8
First Page : 1848
Last Page : 1853
Authors : Ouvry G, Berton Y, Bhurruth-Alcor Y, Bonnary L, Bouix-Peter C, Bouquet K, Bourotte M, Chambon S, Comino C, Deprez B, Duvert D, Duvert G, Hacini-Rachinel F, Harris CS, Luzy AP, Mathieu A, Millois C, Pascau J, Pinto A, Polge G, Reitz A, Reversé K, Rosignoli C, Taquet N, Hennequin LF.
Abstract : Targeting the Tumor Necrosis Factor α signalling with antibodies has led to a revolution in the treatment of psoriasis. Locally inhibiting Tumor Necrosis Factor α Converting Enzyme (TACE or ADAM17) could potentially mimic those effects and help treat mild to moderate psoriasis, without the reported side effect of systemic TACE inhibitors. Efforts to identify new TACE inhibitors are presented here. Enzymatic SAR as well as ADME and physico-chemistry data are presented. This study culminated in the identification of potent enzymatic inhibitors. Suboptimal cellular activity of this series is discussed in the context of previously published results.
|
Inhibition of TACE in human PBMC assessed as inhibition of TNFalpha production
|
Homo sapiens
|
158.49
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Identification of novel TACE inhibitors compatible with topical application.
Year : 2017
Volume : 27
Issue : 8
First Page : 1848
Last Page : 1853
Authors : Ouvry G, Berton Y, Bhurruth-Alcor Y, Bonnary L, Bouix-Peter C, Bouquet K, Bourotte M, Chambon S, Comino C, Deprez B, Duvert D, Duvert G, Hacini-Rachinel F, Harris CS, Luzy AP, Mathieu A, Millois C, Pascau J, Pinto A, Polge G, Reitz A, Reversé K, Rosignoli C, Taquet N, Hennequin LF.
Abstract : Targeting the Tumor Necrosis Factor α signalling with antibodies has led to a revolution in the treatment of psoriasis. Locally inhibiting Tumor Necrosis Factor α Converting Enzyme (TACE or ADAM17) could potentially mimic those effects and help treat mild to moderate psoriasis, without the reported side effect of systemic TACE inhibitors. Efforts to identify new TACE inhibitors are presented here. Enzymatic SAR as well as ADME and physico-chemistry data are presented. This study culminated in the identification of potent enzymatic inhibitors. Suboptimal cellular activity of this series is discussed in the context of previously published results.
