129776-60-9

Upstream product

• 129739-13-5 tert-butyl 3-(R)-benzyloxycarbonyl-5-methylhexanoate 
• 100-51-6 benzyl alcohol 
• 113543-30-9 (S)-4-benzyl-3-(4-methylpentanoyl)oxazolidin-2-one 
• 646-07-1 4-Methylpentanoic acid 
• 38136-29-7 4-methylvaleroyl chloride 
• 144287-83-2 (R)-tert-butyl 3-((S)-4-benzyl-2-oxooxazolidine-3-carbonyl)-5-methylhexanoate 

Downstream Products

• 886057-11-0 benzyl 2-(R)-isobutyl-3-(N-tert-butoxycarbonyl-N-(tert-butyldimethylsilyloxy)carbamoyl)-propionate 
• 886057-13-2 pentafluorophenyl 2-(R)-isobutyl-3-(N-tert-butoxycarbonyl-N-(tert-butyl-dimethylsilyloxy)carbamoyl)propionate 
• 886057-21-2 N¹-{1-[5-(5-amino-1-carbamoyl-pentylcarbamoyl)-pentylcarbamoyl]-2-phenyl-ethyl}-N⁴-hydroxy-2-isobutyl-succinamide 
• 142380-13-0 benzyl (2R)-2-(octahydroazocin-1-ylcarbonylmethyl)-4-methylvalerate 
• 179169-29-0 2-[(R)-1-((R)-2-Cyclohexylcarbamoylmethyl-4-methyl-pentanoylamino)-2-(1-methyl-1H-indol-3-yl)-ethyl]-5-methyl-oxazole-4-carboxylic acid benzyl ester 
• 179169-34-7 2-[(R)-1-((R)-2-Cyclohexylcarbamoylmethyl-4-methyl-pentanoylamino)-2-(1-methyl-1H-indol-3-yl)-ethyl]-5-methyl-1H-imidazole-4-carboxylic acid benzyl ester 
• 142380-46-9 N-cyclohexyl-(3R)-3-carboxy-5-methylhexanamide 
• 151667-50-4 3-(R)-benzyloxycarbonyl-5-methylhexanoic acid chloride 
• 142380-12-9 (R)-2-Cyclohexylcarbamoylmethyl-4-methyl-pentanoic acid benzyl ester 

Relevant academic research and scientific papers

Chemical Tools for Selective Activity Profiling of Endogenously Expressed MMP-14 in Multicellular Models

Matrix metalloproteases (MMPs) are a large family of zinc-dependent endopeptidases involved in a diverse set of physiological and pathological processes, most notably in cancer. Current methods for imaging and quantifying MMP activity lack sufficient selectivity and spatiotemporal resolution to allow studies of specific MMP function in vivo. Previously, we reported a strategy for selective targeting of MMPs by engineering a functionally silent cysteine mutation that enables highly specific covalent modification by a designed activity-based probe. Here, we describe the translation of that technology into a mouse model of breast cancer and subsequent demonstration of the utility of the approach for studies of MMP-14 activation in the tumor microenvironment. Using this approach, we find that MMP-14 is active in late stage tumors and is predominantly associated with stromal cell populations that have been activated by specific signaling molecules (e.g., TGFβ) produced by tumor cells. Our data demonstrate the applicability of this approach for studies of MMP function in whole organisms and identify important regulatory mechanisms for MMP-14 activity in the tumor microenvironment.

Chemical Tools for Selective Activity Profiling of Endogenously Expressed MMP-14 in Multicellular Models

Matrix metalloproteases (MMPs) are a large family of zinc-dependent endopeptidases involved in a diverse set of physiological and pathological processes, most notably in cancer. Current methods for imaging and quantifying MMP activity lack sufficient selectivity and spatiotemporal resolution to allow studies of specific MMP function in vivo. Previously, we reported a strategy for selective targeting of MMPs by engineering a functionally silent cysteine mutation that enables highly specific covalent modification by a designed activity-based probe. Here, we describe the translation of that technology into a mouse model of breast cancer and subsequent demonstration of the utility of the approach for studies of MMP-14 activation in the tumor microenvironment. Using this approach, we find that MMP-14 is active in late stage tumors and is predominantly associated with stromal cell populations that have been activated by specific signaling molecules (e.g., TGFβ) produced by tumor cells. Our data demonstrate the applicability of this approach for studies of MMP function in whole organisms and identify important regulatory mechanisms for MMP-14 activity in the tumor microenvironment.

CALPAIN MODULATORS AND METHODS OF PRODUCTION AND USE THEREOF

The present technology relates to compounds, kits, compositions, and methods useful for the treatment of fibrotic disease. In some aspects, the present technology provides for treatment of various diseases or disorders associated or mediated, at least in part, by calpains, such as CAPN1, CAPN2, and/or CAPN9. The present technology is generally applicable to compounds which inhibit myofibroblast differentiation.

A dual inhibitor of matrix metalloproteinases and a disintegrin and metalloproteinases, [18F]FB-ML5, as a molecular probe for non-invasive MMP/ADAM-targeted imaging

Background Numerous clinical studies have shown a correlation between increased matrix metalloproteinase (MMP)/a disintegrin and metalloproteinase (ADAM) activity and poor outcome of cancer. Various MMP inhibitors (MMPIs) have been developed for therapeutic purposes in oncology. In addition, molecular imaging of MMP/ADAM levels in vivo would allow the diagnosis of tumors. We selected the dual inhibitor of MMPs and ADAMs, ML5, which is a hydroxamate-based inhibitor with affinities for many MMPs and ADAMs. ML5 was radiolabelled with 18F and the newly obtained radiolabelled inhibitor was evaluated in vitro and in vivo. Materials and methods ML5 was radiolabelled by direct acylation with N-succinimidyl-4-[18F]fluorobenzoate ([18F]SFB) for PET (positron emission tomography). The resulting radiotracer [18F]FB-ML5 was evaluated in vitro in human bronchial epithelium 16HBE cells and breast cancer MCF-7 cells. The non-radioactive probe FB-ML5 and native ML5 were tested in a fluorogenic inhibition assay against MMP-2, -9, -12 and ADAM-17. The in vivo kinetics of [18F]FB-ML5 were examined in a HT1080 tumor-bearing mouse model. Specificity of probe binding was examined by co-injection of 0 or 2.5 mg/kg ML5. Results ML5 and FB-ML5 showed high affinity for MMP-2, -9, -12 and ADAM-17; indeed IC50 values were respectively 7.4 ± 2.0, 19.5 ± 2.8, 2.0 ± 0.2 and 5.7 ± 2.2 nM and 12.5 ± 3.1, 31.5 ± 13.7, 138.0 ± 10.9 and 24.7 ± 2.8 nM. Radiochemical yield of HPLC-purified [18F]FB-ML5 was 13-16% (corrected for decay). Cellular binding of [18F]FB-ML5 was reduced by 36.6% and 27.5% in MCF-7 and 16HBE cells, respectively, after co-incubation with 10 μM of ML5. In microPET scans, HT1080 tumors exhibited a low and homogeneous uptake of the tracer. Tumors of mice injected with [18F]FB-ML5 showed a SUVmean of 0.145 ± 0.064 (n = 6) which decreased to 0.041 ± 0.027 (n = 6) after target blocking (p 18F. [18F]FB-ML5 demonstrated rather low binding in ADAM-17 overexpressing cell lines. [18F]FB-ML5 uptake showed significant reduction in the HT1080 tumor in vivo after co-injection of ML5. [18F]FB-ML5 may be suitable for the visualization/quantification of diseases overexpressing simultaneously MMPs and ADAMs.

A peptide hydroxamate library for enrichment of metalloproteinases: Towards an affinity-based metalloproteinase profiling protocol

A compound library of 96 enantiopure N-terminal succinyl hydroxamate functionalized peptides was synthesized on solid phase. All compounds were tested for their inhibitory potential towards MMP-9, MMP-12 and ADAM-17, which led to the identification of both broad spectrum inhibitors and metalloproteinase-selective ones. Eight potent and less potent inhibitors were immobilized on Sepharose beads and evaluated in solid-phase enrichment of active MMP-9, MMP-12 and ADAM-17. In addition, one of these inhibitors was used for solid-phase enrichment of endogenous ADAM-17 from a complex proteome (a lysate prepared from cultured A549 cells). This journal is The Royal Society of Chemistry.

Solid-phase synthesis of succinylhydroxamate peptides: Functionalized matrix metalloproteinase inhibitors

A novel solid-phase synthesis strategy toward succinylhydroxamate peptides, using an appropriately protected hydroxamate building block, is described. Rapid and efficient access is gained to amine-functionalized peptides, which can be decorated with, for instance, a fluorescent label. In addition, we demonstrate an on-resin synthesis of a biotinylated photoactivatable hydroxamate peptide, which can be used as an activity-based probe for matrix metalloproteinases and ADAMs.

Peptide compound and its preparation

Novel peptides of the formula (I") STR1 in which R1 is hydrogen or acyl, R2c is lower alkyl, R3c is optionally N-substituted indolylmethyl, R4 is hydrogen, lower alkyl, C6-10 ar(lower)alkyl, amino(lower)alkyl, protected amino (lower)alkyl, carboxy(lower)alkyl, protected carboxy(lower)alkyl or optionally substituted heterocyclic (lower)alkyl, R5 is carboxy, protected carboxy, carboxy(lower)alkyl or protected carboxy(lower)alkyl, R7 is hydrogen or lower alkyl, and A is --O--, --NH--, lower alkylamino or lower alkylene, or a pharmaceutically acceptable salt thereof are disclosed. Additionally, the preparation of such peptides is described. The peptides are used to treat endothelin mediated diseases such as hypertension.