Skiles, Jerry W.; Miao, Clara; Sorcek, Ronald; Jacober, Stephen; Mui, Philip W.; Chow, Grace; Weldon, Steve M.; Possanza, Genus; Skoog, Mark published their research in Journal of Medicinal Chemistry on December 25 ,1992. The article was titled 《Inhibition of human leukocyte elastase by N-substituted peptides containing α,α-difluorostatone residues at P1》.Name: (S)-N-Methyl-N-methoxy-2-(tert-butoxycarbonylamino)-4-methylpentanamide The article contains the following contents:
A series of tripeptides which contain α,α-difluorostatone residues at P1-P1′ and span the S3-S1′ subsites have been shown to be potent inhibitors of human leukocyte elastase (HLE). The tripeptides described contain the nonproteinogenic achiral residue N-(2,3-dihydro-1H-inden-2-yl)glycine at the P2-position. This residue has previously been shown in the case of HLE to be a good bioisosteric replacement for L-proline. Of the peptides prepared, those which contain the α,α-difluoromethylene ketone derivative of L-valine (difluorostatone) are the preferred residue at the P1-primary specificity position. Substitution at P1 by the corresponding a,α-difluoromethylene ketones of L-leucine and L-phenylalanine gives inactive compounds Of the tripeptides described the most potent in vitro compound is peptide I (IC50 = 0.635 μM). It is presumed that the inhibitor I interacts with the S3-S1′ binding regions of HLE. Addnl. extended binding inhibitors were prepared which interact with the S3-S3′ binding subsites of HLE. In order to effect interaction with the S1′-S3′ substitutes of HLE, the leaving group side of cleaved peptides, spacers based upon Gly-Gly, and those linked via the Nε of L-lysine were utilized. One of the most potent extended compounds (P3-P3′) in vitro is peptide II (IC50 = 0.057 μM). The described in vitro active inhibitors were also evaluated in hamsters in an elastase-induced pulmonary hemorrhage (EPH) model. In this model, intratracheal administration of peptide III, 5 min prior to HLE challenge (10 μg, it.) effectively inhibited hemorrhage (94.6%) in a dose-dependent manner. The described α,α-difluoromethylene ketone inhibitors are assumed to act as transition-state analogs. The inhibition process presumably acts via hemiketal formation with the active site Ser195 of HLE, and is facilitated by the strongly electron withdrawing effect of the α,α-difluoromethylene functionality.(S)-N-Methyl-N-methoxy-2-(tert-butoxycarbonylamino)-4-methylpentanamide(cas: 87694-50-6Name: (S)-N-Methyl-N-methoxy-2-(tert-butoxycarbonylamino)-4-methylpentanamide) was used in this study.
(S)-N-Methyl-N-methoxy-2-(tert-butoxycarbonylamino)-4-methylpentanamide(cas: 87694-50-6) belongs to amides.Name: (S)-N-Methyl-N-methoxy-2-(tert-butoxycarbonylamino)-4-methylpentanamide Amides include many other important biological compounds, as well as many drugs like paracetamol, penicillin and LSD. Low-molecular-weight amides, such as dimethylformamide, are common solvents.
Referemce:
Amide – Wikipedia,
Amide – an overview | ScienceDirect Topics