ChemInform Abstract: Design and Synthesis of Potent and Specific Renin Inhibitors Containing Difluorostatine, Difluorostatone, and Related Analogues.

Thaisrivongs, Suvit; Pals, Donald T.; Kati, Warren M.; Turner, Steve R.; Thomasco, Lisa M.; Watt, W.

doi:10.1002/chin.198711302

Cited by 15 publications

(23 citation statements)

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“…The weaker binding to pepsin and renin of statones relative to the hydroxy analogues was attributed to the unfavorable equilibrium for hydration of the ketone function. Indeed, peptides containing the more readily hydrated 2,2-difluorostatone moiety (-C(OH)2-CF2-) were subsequently found to be 50-1,000-fold more potent against both porcine pepsin and renin than the nonfluorinated statone analogues (Gelb et al, 1985;Thairivongs et al, 1985Thairivongs et al, , 1986Fearon et al, 1987).…”

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confidence: 99%

Direct observation by X‐ray analysis of the tetrahedral “intermediate” of aspartic proteinases

et al. 1992

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We report the X-ray analysis at 2.0 A resolution for crystals of the aspartic proteinase endothiapepsin (EC 3.4.23.6) complexed with a potent difluorostatone-containing tripeptide renin inhibitor 282). The scissile bond surrogate, an electrophilic ketone, is hydrated in the complex. The pro-(R) (statine-like) hydroxyl of the tetrahedral carbonyl hydrate is hydrogen-bonded to both active-site aspartates 32 and 215 in the position occupied by a water in the native enzyme. The second hydroxyl oxygen of the hydrate is hydrogen-bonded only to the outer oxygen of Asp 32. These experimental data provide a basis for a model of the tetrahedral intermediate in aspartic proteinase-mediated cleavage of the amide bond. This indicates a mechanism in which Asp 32 is the proton donor and Asp 215 carboxylate polarizes a bound water for nucleophilic attack. The mechanism involves a carboxylate (Asp 32) that is stabilized by extensive hydrogen bonding, rather than an oxyanion derivative of the peptide as in serine proteinase catalysis.

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confidence: 99%

Direct observation by X‐ray analysis of the tetrahedral “intermediate” of aspartic proteinases

et al. 1992

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“…23,24 In contrast, difluoro alcohols are only known to inhibit aspartyl proteases. 25,26 These results therefore suggest that γ-secretases are aspartyl proteases.…”

Section: Resultsmentioning

confidence: 72%

“…Difluoro ketones are readily hydrated to closely mimic the transition state of aspartyl protease catalysis, but certain analogues of this type can also inhibit serine and cysteine proteases 23,24. In contrast, difluoro alcohols are only known to inhibit aspartyl proteases 25,26. These results therefore suggest that γ‐secretases are aspartyl proteases.…”

Section: Resultsmentioning

confidence: 99%

Toward the Characterization and Identification of γ‐Secretases Using Transition‐state Analogue Inhibitors

Moore

Diehl

Selkoe

et al. 2000

Annals of the New York Academy of Sciences

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The amyloid‐β protein (Aβ), strongly implicated in the etiology of Alzheimer's disease (AD), is formed from the amyloid‐β precursor protein (APP) through sequential proteolysis by β‐ and γ‐secretases. Cleavage by γ‐secretase takes place within the middle of the single transmembrane region of APP and results primarily in 40‐ and 42‐amino acid Aβ C‐terminal variants, Aβ40 and Aβ42. The latter form of Aβ is highly fibrillogenic, is invariably elevated in autosomal‐dominant forms of AD, and is the major Aβ component found presymptomatically in cerebral deposits. Thus, blocking production of Aβ in general and Aβ42 in particular is considered an important therapeutic goal. We have developed transition‐state analogue inhibitors of γ‐secretase as molecular probes for characterizing the active site of this enzyme, as pharmacological tools for understanding its role in biology, and as affinity labels toward its definitive identification. Specifically, we found that: (1) difluoro ketone and difluoro alcohol peptidomimetics are effective inhibitors of γ‐secretase activity in APP‐transfected cells, strongly suggesting an aspartyl protease mechanism; (2) γ‐secretases that form Aβ40 and Aβ42 are pharmacologically distinct but are nevertheless closely similar; (3) large hydrophobic P1 substituents increase the inhibitory potency of these peptidomimetics, suggesting a large complementary S1 pocket for γ‐secretases; (4) Aβ42 production is increased several fold over control by these γ‐secretase inhibitors after replacement with inhibitor‐free media; (5) a bromoacetamide derivative of one of these analogues continues to inhibit total Aβ and Aβ42 production hours after replacement with compound‐free media and should help identify the target(s) of these protease transition‐state mimics.

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“…A series of enantio-and diastereopure peptides containing different structural analogues of statine was prepared for a comparative inhibition of human plasma renin [37]. For the compounds having general backbone Boc-PheHis-X-Ile-AMP, where X is the StaF 2 or StoF 2 core depicted in figure 1 (R =isopropyl, benzyl, or methylcyclohexyl) and AMP is the 2-pyridylmethylamine moiety, a general trend was found.…”

Section: Reninmentioning

confidence: 94%

Peptidyl Fluoro-Ketones as Proteolytic Enzyme Inhibitors

Sani¹,

Sinisi²,

Viani³

2006

CTMC

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Proteolytic enzymes are involved in many important physiological processes. Because of the critical roles played by these enzymes, aberrations in regulation of their activities can lead to pathological conditions. For this reason, finding inhibitors selective for a proteolytic enzyme that is contributing to a medical problem can be an effective therapeutic strategy. The introduction of fluorine in the backbone of proteolytic enzyme substrates can lead to active and selective inhibitors belonging to the peptidyl fluorinated ketone family. Fluorine not only can influence the mechanism of substrate/enzyme recognition events but also can modify the in vivo profile of the substrate. Although prediction of the total effects of fluorine on the pharmacokinetic parameters can be difficult, the pharmaceutical interest in the synthesis and biological evaluation of peptidyl fluorinated ketones highlights the potential of this family of molecules as therapeutically useful inhibitors.

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ChemInform Abstract: Design and Synthesis of Potent and Specific Renin Inhibitors Containing Difluorostatine, Difluorostatone, and Related Analogues.

Cited by 15 publications

References 1 publication

Direct observation by X‐ray analysis of the tetrahedral “intermediate” of aspartic proteinases

Direct observation by X‐ray analysis of the tetrahedral “intermediate” of aspartic proteinases

Toward the Characterization and Identification of γ‐Secretases Using Transition‐state Analogue Inhibitors

Peptidyl Fluoro-Ketones as Proteolytic Enzyme Inhibitors

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