128018-20-2

Upstream product

• 1161-13-3 N-Cbz-L-Phe 
• 41518-17-6 Z-Phe-O-COO-isoBu 
• 128018-43-9 N-benzyloxycarbonyl-3(S)-amino-1-chloro-4-phenyl-2(S)-butanol 
• 26049-94-5 (S)-benzyl (4-chloro-3-oxo-1-phenylbutan-2-yl)carbamate 
• 128018-44-0 N-benzyloxycarbonyl-3(S)-amino-1,2(S)epoxy-4-phenylbutane 
• 128018-18-8 L-proline tert-butylamide 

Downstream Products

• 128053-39-4 (S)-1-((2R,3S)-3-Amino-2-hydroxy-4-phenyl-butyl)-pyrrolidine-2-carboxylic acid tert-butylamide 

Relevant academic research and scientific papers

An unusual functional group interaction and its potential to reproduce steric and electrostatic features of the transition states of peptidolysis

The donor-acceptor interaction between a tertiary amine and an aldehyde, first observed among a select class of alkaloids, was deliberately established in a peptidomimetic (1a-c) to mimic features of the two principal transition states of peptide hydrolys

HIV protease inhibitors

Combinatorial libraries of HIV and FIV protease inhibitors are characterized by alpha-keto amide or hydroxyethylamine core structures flanked by on one side by substituted pyrrolidines, piperidines, or azasugars and on the other side by phenylalanine, tyrosine, or substituted tyrosines. The libraries are synthesized via a one step coupling reaction. Highly efficacious drug candidates are identified by screening the libraries for binding and inhibitory activity against both HIV and FIV protease. Drug candidates displaying clinically useful activity against both HIV and FIV protease are identified as being potentially resistive against a loss of inhibitory activity due to development of resistant strains of HIV.

Development of a new type of protease inhibitors, efficacious against FIV and HIV variants

Based on the structural analysis of FIV protease and drug-resistant HIV proteases and molecular modeling, a new type of inhibitors with a small P3 residue has been developed. These inhibitors are effective against HIV and its drug-resistant mutants, as well as SIV and FIV. Modification of existing HIV protease inhibitors by reducing the size of the P3 residue has the same effect. This finding provides a new strategy for the development of HIV protease inhibitors effective against the wild-type and drug-resistant mutants. It further supports the use of FIV protease as a useful model for drug-resistant HIV proteases, which often have a more constricted binding region for the P3 group or the combined P3 and P1 groups.

Selectivity in the inhibition of HIV and FIV protease: Inhibitory and mechanistic studies of pyrrolidine-containing α-keto amide and hydroxyethylamine core structures

This paper describes the development of new pyrrolidine-containing α-keto amide and hydroxyethylamine core structures as mechanism based inhibitors of the HIV and FIV proteases. It was found that the α-keto amide core structure 2 is approximately 300-fold better than the corresponding hydroxyethylamine isosteric structure and 1300-fold better than the corresponding phosphinic acid derivative as an inhibitor of the HIV protease. The α-keto amide is however not hydrated until it is bound to the HIV protease as indicated by the NMR study and the X-ray structural analysis. Further analysis of the inhibition activities of hydroxyethylamine isosteres containing modified pyrrolidine derivatives revealed that a cis-methoxy group at C-4 of the pyrrolidine would improve the binding 5- and 25-fold for the trans-isomer. When this strategy was applied to the α-keto amide isostere, a cis-benzyl ether at C-4 was found to enhance binding 3-fold. Of the core structures prepared as inhibitors of the HIV protease, none show significant inhibitory activity against the mechanistically identical FIV protease, and additional complementary groups are needed to improve inhibition.