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 structurally similar alpha-hydroxy esters (32 and 30, I50's = 5.3 and 4.7 nM, respectively) and alpha-hydroxy ketones (41 and 42, I50 = 23 and 15 nM, respectively) were 150-300-fold more active. The hydrating capability of the activated ketone functionality was important for intrinsic potency in the case of trifluoromethyl ketones, as illustrated by the significantly better activity of trifluoromethyl ketone 13 (I50 = 250 nM) compared to its alcohol analog 12 (I50 = 4000 nM). It was however unimportant for the alpha-keto ester (20 and 31, I50 = 15 and 4.1 nM, respectively) and alpha-diketone (43 and 44, I50 = 52 and 28 nM, respectively) based inhibitors, since their activity was essentially similar to that of the corresponding alcohols. These results collectively suggest that, whereas the trifluoromethyl ketones derive their renin inhibitory potency primarily from their ability to become hydrated, this is not a critical feature for the activity of alpha-dicarbonyl-based inhibitors. The alpha-keto ester and alpha-diketone based renin inhibitors benefit predominantly from the hydrophobic and/or H-bonding type binding interactions of the neighboring ester or acyl group itself, rather than the ability of this group to deactivate the adjacent ketone group and thereby make it susceptible to hydration.

Further Studies on Nociceptin-Related Peptides: Discovery of a New Chemical Template with Antagonist Activity on the Nociceptin Receptor

“…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.…”

“…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.…”

Peptidyl Fluoro-Ketones as Proteolytic Enzyme Inhibitors

“…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.…”

“…Bristol -Myers Squibb [5] proposed inhibitors based on differently activated ketones (EW = CF 3 , CO 2 R, or COR - Fig. (10), structure A).…”

Catalytic Asymmetric Synthesis of Fluoroorganic Compounds: Mukaiyama-Aldol and Henry Reactions

“…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.…”