119601-52-4

Upstream product

• 55112-42-0 4-methylpiperazine-1-carbonyl chloride monohydrochloride 
• 2462-32-0 L-phenylalanine benzyl ester hydrochloride 
• 109-01-3 1-methyl-piperazine 
• 119624-66-7 benzyl (2S)-2-isocyanato-3-phenylpropanoate 

Downstream Products

• 233277-99-1 4-Methyl-piperazine-1-carboxylic acid [(S)-1-((E)-(S)-3-benzenesulfonyl-1-phenethyl-allylcarbamoyl)-2-phenyl-ethyl]-amide 
• 115766-11-5 N-[(4-methyl-1-piperazinyl)carbonyl]-L-phenylalanine 

Relevant academic research and scientific papers

Self-Masked Aldehyde Inhibitors: A Novel Strategy for Inhibiting Cysteine Proteases

Cysteine proteases comprise an important class of drug targets, especially for infectious diseases such as Chagas disease (cruzain) and COVID-19 (3CL protease, cathepsin L). Peptide aldehydes have proven to be potent inhibitors for all of these proteases. However, the intrinsic, high electrophilicity of the aldehyde group is associated with safety concerns and metabolic instability, limiting the use of aldehyde inhibitors as drugs. We have developed a novel class of self-masked aldehyde inhibitors (SMAIs) for cruzain, the major cysteine protease of the causative agent of Chagas disease - Trypanosoma cruzi. These SMAIs exerted potent, reversible inhibition of cruzain (Ki? = 18-350 nM) while apparently protecting the free aldehyde in cell-based assays. We synthesized prodrugs of the SMAIs that could potentially improve their pharmacokinetic properties. We also elucidated the kinetic and chemical mechanism of SMAIs and applied this strategy to the design of anti-SARS-CoV-2 inhibitors.

Proteomic profiling and potential cellular target identification of K11777, a clinical cysteine protease inhibitor, in Trypanosoma brucei

We report herein the design, synthesis and application of K11777-derived activity-based probes (ABPs) allowing in situ profiling and identification of potential cellular targets of K11777 in Trypanosoma brucei.

Potency and selectivity of P2/P3-modified inhibitors of cysteine proteases from trypanosomes

A systematic study of P2 and P3 substitution in a series of vinyl sulfone cysteine protease inhibitors is described. The introduction of a methyl substituent in the P2 phenylalanine aryl ring had a favorable effect on protease inhibition and conferred modest selectivity for rhodesain over cruzain. Rhodesain selectivity could be enhanced further by combining these P2 modifications with certain P3 amide substituents.

pH dependence of inhibitors targeting the occluding loop of cathepsin B

Potent and selective cathepsin B inhibitors have previously been synthesized based upon the natural product cysteine protease inhibitor E-64. X-ray crystal data indicates that these compounds interact through their free carboxylate with the positively charged histidine residues located on the prime-side of the active site within the occluding loop of cathepsin B. Herein, we examine the pH dependence of two prime-side-binding compounds. In each case there is a dramatic decrease in kinact/KI as the pH is raised from 4 to 7.8 corresponding to a single ionization of pKa 4.4. These results suggest that targeting of the occluding loop of cathepsin B may be a poor inhibitor design strategy if the enzyme environment has a pH greater than 5.5. However, this type of inhibitor may be a useful tool to help elucidate the role and the environment of cathepsin B in invading tumors.

RENIN INHIBITOR PEPTIDE COMPOUNDS, A PROCESS FOR THE PREPARATION THEREOF AND PHARMACEUTICAL COMPOSITION COMPRISING THE SAME

A compound of the formula: STR1 wherein R 1 is aryl optionally substituted with a substituent selected from the group consisting of halogen and halo(lower)alkyl; lower alkyl or cyclo(lower) alkyl; andR 2 is hydrogen or lower alkyl, or R. sup.1 and R 2 are taken together with the attached nitrogen atom to form a heterocyclic group optionally substituted with a substituent selected from the group consisting of lower alkyl and esterified carboxy, R 3 is hydrogen or lower alkyl, andR 4 is lower alkyl,and its pharmaceutically acceptable salt, a process for the preparation thereof and pharmaceutical composition comprising the same.