1993
DOI: 10.1021/jm00069a001
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Activated ketone based inhibitors of human renin

Abstract: Application of the concept of activated ketones to the design of novel and potent transition-state analog inhibitors of the aspartyl protease renin is described. Three different classes of peptidic activated ketones were synthesized: 1,1,1-trifluoromethyl ketones, alpha-keto esters, and alpha-diketones. The corresponding alcohols were also evaluated as renin inhibitors in each series. While the trifluoromethyl alcohol 12 (I50 = 4000 nM) was equipotent to the simple methyl alcohol 7 (I50 = 3200 nM), the structu… Show more

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Cited by 72 publications
(42 citation statements)
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References 23 publications
(61 reference statements)
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“…Boc-protected amino aldehydes were prepared by the reduction of the Weinreb amide. 39 Peptides were assembled using Fmocprotected amino acid (4 equiv), DIPCDI (4 equiv), and HOBt (4 equiv) as coupling agents for 1 h for each coupling. Side chain protecting groups used were Pmc for Arg, Trt for Asn and Gln, Boc for Lys, and tBu for Ser and Thr.…”
Section: Resultsmentioning
confidence: 99%
See 1 more Smart Citation
“…Boc-protected amino aldehydes were prepared by the reduction of the Weinreb amide. 39 Peptides were assembled using Fmocprotected amino acid (4 equiv), DIPCDI (4 equiv), and HOBt (4 equiv) as coupling agents for 1 h for each coupling. Side chain protecting groups used were Pmc for Arg, Trt for Asn and Gln, Boc for Lys, and tBu for Ser and Thr.…”
Section: Resultsmentioning
confidence: 99%
“…The crude Boc-amino aldehyde was used immediately, without further purification, for the synthesis of compounds 1b-8b. The analytical data of: Boc-Leu-CHO and Boc-Phe-CHO, 56 Boc-Cha-CHO, 39 Boc-N-alkylglycines. The N-substituted glycine ethyl esters were prepared following the procedure of Skiles et al 58 by treatment of known primary amines: isobutylamine and cyclohexylmethylamine with ethyl bromoacetate or alternatively by reductive alkylation of 4-hydroxybenzaldehyde or p-tolualdehyde with glycine ethyl esters in the presence of NaCNBH3.…”
Section: Methodsmentioning
confidence: 99%
“…This versatility arises from the fact that the keto moiety exists as a hydrate in aqueous media and can thus directly serve as a transition-state analogue and/or react with a nucleophilic residue to form a reversible, hemiacetal-type intermediate [5]. The most widely used activated ketones belong to α-keto ester, α-diketone, α-chloro ketone [6], α-2-benzoxazole and α-2-oxazole ketone [7], α-diazo ketone [8], α-ketomethylsulfonium salt [9], α-[(arylacyl)oxy]methyl ketone, and α-(aryloxy)-methyl ketone [10] categories.…”
Section: Activated Ketonesmentioning
confidence: 99%
“…Bristol -Myers Squibb [5] proposed inhibitors based on differently activated ketones (EW = CF 3 , CO 2 R, or COR - Fig. (10), structure A).…”
Section: Reninmentioning
confidence: 99%
“…The catalytic asymmetric nitroaldol reaction of 2,2-difluoroaldehydes was applied as a key step to the synthesis of a biologically significant molecule in enantiomerically pure form. The introduction of fluorine atoms into the /^position to a hydroxyl group enhances its acidity, making it a better proton donor to the active sites of enzymes and receptors (48). j8,j5-Difluoro peptidyl alcohols also act as reversible protease inhibitors.…”
Section: Catalytic Asymmetric Nitroaldol (Henry) Reaction Of 22-difimentioning
confidence: 99%