30293-88-0

Upstream product

• 7517-19-3 methyl (L)-leucinate hydrochloride 
• 503-38-8 trichloromethyl chloroformate 
• 124-38-9 carbon dioxide 
• 32315-10-9 bis(trichloromethyl) carbonate 
• 75-44-5 phosgene 
• 2666-93-5 (S)-Leu-OMe 
• 61-90-5 L-leucine 
• 24424-99-5 di-tert-butyl dicarbonate 

Downstream Products

• 57699-95-3 C₁₇H₂₅N₃O₅ 
• 57700-01-3 Boc-AzaPhe-Leu-OMe 
• 112382-87-3 N-<(1S)-(1-methoxycarbonyl-3-methylbutyl)carbamoyl>-L-valyl-L-valyl-α-azanorvaline benzyl ester 
• 109953-36-8 N-<(1-methoxycarbonyl-3-methylbutyl)carbamoyl>-L-valyl-L-alanyl-α-aza-alanine benzyl ester 
• 112383-09-2 N-<(1S)-(1-methoxycarbonyl-3-methylbutyl)carbamoyl>-L-valylglycyl-Ψ(CH2S)-D-leucine benzyl ester 
• 112383-05-8 N-<(1S)-(1-methoxycarbonyl-3-methylbutyl)carbamoyl>-L-leucylglycyl-Ψ(CH2S)-D-leucine benzyl ester 
• 112383-05-8 N-<(1S)-(1-methoxycarbonyl-3-methylbutyl)carbamoyl>-L-leucylglycyl-Ψ(CH2S)-leucine benzyl ester 
• 733744-92-8 (S)-2-[3-((2R,3S)-3-tert-Butoxycarbonylamino-2-hydroxy-4-phenyl-butyl)-3-methyl-ureido]-4-methyl-pentanoic acid methyl ester 
• 853904-96-8 (S)-2-[3-Benzyl-3-((2R,3R)-3-tert-butoxycarbonylamino-2-hydroxy-4-phenyl-butyl)-ureido]-4-methyl-pentanoic acid methyl ester 
• 500783-13-1 C₄₂H₄₅N₅O₄ 
• 500782-81-0 C₄₄H₄₉N₅O₄ 
• 500783-14-2 C₄₃H₄₇N₅O₄ 
• 500783-04-0 C₄₇H₄₉N₅O₄ 
• 500783-06-2 C₄₃H₄₆FN₅O₄ 

Relevant academic research and scientific papers

Synthesis of N-Acylamino-Acid Derivatives of Cytisine

N-acylamino-acid derivatives of cytisine were prepared by reacting cytisine with methyl esters of aminoacid isocyanates.

Topographically constrained aromatic α-aza-amino acids. Part 2. New azaTic-containing peptides: Synthesis, conformation, and intramolecular NH···N interaction

The new pseudodipeptide Boc-azaTic-Leu-OMe (1), incorporating the conformationally and topographically constrained 3,4-dihydro-2(1H)- phthalazinecarboxylic acid (azaTic) residue, has been synthesized together with the three related models Boc-azaTic-NHMe

Design of Transmembrane Mimetic Structural Probes to Trap Different Stages of γ-Secretase-Substrate Interaction

The transmembrane domain (TMD) of the amyloid precursor protein of Alzheimer's disease is cut processively by γ-secretase through endoproteolysis and tricarboxypeptidase "trimming". We recently developed a prototype substrate TMD mimetic for structural analysis - composed of a helical peptide inhibitor linked to a transition-state analogue - that simultaneously engages a substrate exosite and the active site and is pre-organized to trap the carboxypeptidase transition state. Here, we developed variants of this prototype designed to allow visualization of transition states for endoproteolysis, TMD helix unwinding, and lateral gating of the substrate, identifying potent inhibitors for each class. These TMD mimetics exhibited non-competitive inhibition and occupy both the exosite and the active site, as demonstrated by inhibitor cross-competition experiments and photoaffinity probe binding assays. The new probes should be important structural tools for trapping different stages of substrate recognition and processing via ongoing cryo-electron microscopy with γ-secretase, ultimately aiding rational drug design.

Design of Substrate Transmembrane Mimetics as Structural Probes for ?3-Secretase

?3-Secretase is a membrane-embedded aspartyl protease complex central in biology and medicine. How this enzyme recognizes transmembrane substrates and catalyzes hydrolysis in the lipid bilayer is unclear. Inhibitors that mimic the entire substrate transmembrane domain and engage the active site should provide important tools for structural biology, yielding insight into substrate gating and trapping the protease in the active state. Here, we report transmembrane peptidomimetic inhibitors of the ?3-secretase complex that contain an N-terminal helical peptide region that engages a substrate docking exosite and a C-terminal transition-state analog moiety targeted to the active site. Both regions are required for stoichiometric inhibition of ?3-secretase. Moreover, enzyme inhibition kinetics and photoaffinity probe displacement experiments demonstrate that both the docking exosite and the active site are engaged by the bipartite inhibitors. The solution conformations of these potent transmembrane-mimetic inhibitors are similar to those of bound natural substrates, suggesting these probes are preorganized for high-affinity binding and should allow visualization of the active ?3-secretase complex, poised for intramembrane proteolysis, by cryo-electron microscopy.

Structure-Guided Optimization of Dipeptidyl Inhibitors of Norovirus 3CL Protease

Acute gastroenteritis caused by noroviruses has a major impact on public health worldwide in terms of morbidity, mortality, and economic burden. The disease impacts most severely immunocompromised patients, the elderly, and children. The current lack of approved vaccines and small-molecule therapeutics for the treatment and prophylaxis of norovirus infections underscores the need for the development of norovirus-specific drugs. The studies described herein entail the use of the gem-dimethyl moiety as a means of improving the pharmacological activity and physicochemical properties of a dipeptidyl series of transition state inhibitors of norovirus 3CL protease, an enzyme essential for viral replication. Several compounds were found to be potent inhibitors of the enzyme in biochemical and cell-based assays. The pharmacological activity and cellular permeability of the inhibitors were found to be sensitive to the location of the gem-dimethyl group.

COMPOUNDS AND METHODS FOR TREATING CANCER, VIRAL INFECTIONS, AND ALLERGIC CONDITIONS

The present invention generally relates to compounds that are useful for inhibiting one or more trypsin-like S1 serine proteases, HGFA, matriptase, hepsin, KLK5 and/or TMPRSS2 as well as cysteine proteases including trypsin-like cysteine proteases (e.g. C

Piperidine carbamate peptidomimetic inhibitors of the serine proteases HGFA, matriptase and hepsin

Matriptase and hepsin are type II transmembrane serine proteases (TTSPs). Along with related S1 trypsin like serine protease HGFA (hepatocyte growth factor activator), their unregulated proteolytic activity has been associated with cancer including tumor progression and metastasis. These three proteases have two substrates in common, hepatocyte growth factor (HGF) and macrophage stimulating protein (MSP), the ligands for MET and recepteur d'origine nantais (RON) receptor tyrosine kinases. Mechanism-based tetrapeptide and benzamidine inhibitors of these proteases have been shown to block HGF/MET and MSP/RON cancer cell signaling. Herein, we have rationally designed a new class of peptidomimetic hybrid small molecule piperidine carbamate dipeptide inhibitors comparable in potency to much larger tetrapeptides. We have identified multiple compounds which have potent activity against matriptase and hepsin and with excellent selectivity over the off-target serine proteases factor Xa and thrombin.

Structure-guided design of potent and permeable inhibitors of MERS coronavirus 3CL protease that utilize a piperidine moiety as a novel design element

There are currently no approved vaccines or small molecule therapeutics available for the prophylaxis or treatment of Middle East Respiratory Syndrome coronavirus (MERS-CoV) infections. MERS-CoV 3CL protease is essential for viral replication; consequently, it is an attractive target that provides a potentially effective means of developing small molecule therapeutics for combatting MERS-CoV. We describe herein the structure-guided design and evaluation of a novel class of inhibitors of MERS-CoV 3CL protease that embody a piperidine moiety as a design element that is well-suited to exploiting favorable subsite binding interactions to attain optimal pharmacological activity and PK properties. The mechanism of action of the compounds and the structural determinants associated with binding were illuminated using X-ray crystallography.

Design, synthesis, and evaluation of a novel series of macrocyclic inhibitors of norovirus 3CL protease

Norovirus infections have a major impact on public health worldwide, yet there is a current dearth of norovirus-specific therapeutics and prophylactics. This report describes the discovery of a novel class of macrocyclic inhibitors of norovirus 3C-like pr

SMALL MOLECULE THERAPEUTIC INHIBITORS AGAINST PICORNAVIRUSES, CALICIVIRUSES, AND CORONAVIRUSES

Antiviral protease inhibitors are disclosed, along with related antiviral dipeptidyl compounds, macrocyclic derivatives thereof, and methods of using the same to treat or prevent viral infection and disease from coronaviruses, caliciviruses, and picornaviruses.