Design and synthesis of potent and specific renin inhibitors containing difluorostatine, difluorostatone, and related analogs

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

doi:10.1021/jm00160a048

Cited by 139 publications

(82 citation statements)

References 4 publications

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“…The other inhibitors in Table 2 Table 2); Cbz is benzyloxycarbonyl. Compounds 19,27, and 30 were prepared using published procedures (20)(21)(22). The synthesis of compounds [20][21][22][23][24][25][26]28, and 29 will be described elsewhere (G.B.D., unpublished data).…”

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Inhibition of human immunodeficiency virus 1 protease in vitro: rational design of substrate analogue inhibitors.

Dreyer¹,

Metcalf²,

Tomaszek³

et al. 1989

Proc. Natl. Acad. Sci. U.S.A.

192

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Inhibitors of the protease from human immunodeficiency virus 1 (HIV-1) were designed, synthesized, and kinetically characterized. Analogues of a heptapeptide substrate of HIV-1 protease with sequence similar to the pl7-p24 cleavage site in the natural substrate, Pr55519, were synthesized in which the scissile dipeptide bond was replaced with bonds from six categories of stable mimics of an aspartic proteolysis transition state or intermediate. These mimics included an analogue of statine, hydroxyethylene isosteres, two categories of phosphinic acids, a reduced amide isostere, and an a,a-difluoroketone. The resulting peptide analogues were linear competitive inhibitors of purified recombinant HIV-1 protease with inhibition constants ranging from 18 nM to 40 ,uM depending on the type of inhibitor. A truncated inhibitor, an analogue of a hexapeptide, retained full inhibitory potency. The most potent inhibitors, containing the hydroxyethylene isostere, effectively blocked the proteolytic processing of a recombinant form of Pr55s'9 by HIV-1 protease in a cell-free assay.

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Section: Methodsmentioning

confidence: 99%

“…The synthesis of compounds [20][21][22][23][24][25][26]28, and 29 will be described elsewhere (G.B.D., unpublished data). The peptide analogues (Table 2) were synthesized from compounds [19][20][21][22][23][24][25][26][27][28][29][30] tTo whom reprint requests should be addressed.…”

Section: Methodsmentioning

confidence: 99%

Inhibition of human immunodeficiency virus 1 protease in vitro: rational design of substrate analogue inhibitors.

Dreyer¹,

Metcalf²,

Tomaszek³

et al. 1989

Proc. Natl. Acad. Sci. U.S.A.

192

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“…Fluoromethyl ketones have been described as inhibitors of serine, cysteine, and aspartic acid proteases, including elastase, Cathepsin B, renin, and HIV protease. [14][15][16][17][18][19][20][21][22] Two peptide trifluoromethyl ketones have been synthesized based on the approach outlined in Fig. 3.…”

Section: C)mentioning

confidence: 99%

N-to-C Solid-Phase Peptide and Peptide Trifluoromethylketone Synthesis Using Amino Acid tert-Butyl Esters.

Gutheil

2002

CHEMICAL & PHARMACEUTICAL BULLETIN

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Solid-phase peptide synthesis (SPPS) in the N-to-C direction (inverse SPPS), opposite to the classical C-to-N direction of peptide synthesis,2) provides the synthetically versatile peptide C-terminal carboxyl group for further modification into C-terminally modified peptide mimetics. These are of general interest as potential bioactive agents, and of particular interest in the search for potent and specific protease inhibitors. In addition, the ability to elaborate the C-terminus on the solid-phase would facilitate the synthesis of combinatorial libraries of peptide mimetics.3-5) Several strategies for inverse SPPS have been described.6-10) Recently described strategies for inverse SPPS include using amino acid 9-fluorenylmethyl esters, 8) amino acid tri-tert-butyloxysilyl esters, 9) and amino acid allyl esters. 10) These strategies appear less than ideal, since suitable amino acid derivatives are not generally available commercially and can be difficult to prepare, and due to instability of reactants and/or intermediates. Amino acid tert-butyl esters are easily prepared, stable, and a large selection are commercially available. Another advantage is that the well established chemistry, instrumentation, and side chain protecting groups developed for the analogous Boc strategy for normal phase SPPS syntheses can be used as guides in the development and application of amino acid tert-butyl ester based inverse SPPS. This report describes an amino acid tert-butyl ester based strategy for inverse SPPS of peptides and peptide trifluoromethylketones.Our initial strategy for inverse SPPS used succinylated Pam resin, as illustrated by an example synthesis of the model peptide Suc-Ala-Leu-Pro-Phe (1) (Fig. 1). To compare different coupling procedures this model peptide was synthesized with dicyclohexylcarbodiimide (DCC)/N-hydroxybenztriazol (HOBT), O-benzotriazol-1-yl-1,1,3,3- and O-7-azabenzotriazol-1-yl-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU)/2,4,6-trimethylpyridine (TMP) based coupling methods. With HBTU/DIEA both in situ and preactivation protocols were tested. After completion of chain assembly succinylated peptide was released from the solid support by treatment with trifluoromethanesulfonic acid (TFMSA)/trifluoroacetic acid (TFA), and products were analyzed by liquid chromatography (LC)/MS. Coupling with DCC/HOBT gave the target peptide (60%) and two deletion peptides-Suc-Ala-Leu-Pro (20%) and Suc-AlaPro-Phe (20%)-resulting from incomplete incorporation of Phe and Leu residues respectively. HBTU/DIEA and HATU/TMP coupling methods yielded high purity (Ͼ80%) target peptide.To compare the effect of preactivation (resin attached carboxyl group activated prior to addition of the amino acid tert-butyl ester) with in situ activation (all reagents mixed together nearly at once) on racemization, peptide samples were synthesized with HBTU/DIEA both with in situ and preactivation, and analyzed for racemization using Marfey's reagent 11,12) (1 a) and 1 b) in Table 1). The first and second residues underwent subst...

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“…Sham, Abbott Laboratories, Pharmaceutical Discovery Division, Abbott Park, IL 60064, USA reduced amide [5] and a hydroxyethylene isostere [6] at the scissile Leul°-Val tl amide bond. Renin inhibitors incorporating the amino acid statine [7] and more recently difluorostatine and difluorostatone [8] have also been described. The high level of interest in preparing fluoro ketone analogs as inhibitors of proteolytic enzymes [8][9][10] prompted us to report our work in this area.…”

Section: Introductionmentioning

confidence: 99%

“…Renin inhibitors incorporating the amino acid statine [7] and more recently difluorostatine and difluorostatone [8] have also been described. The high level of interest in preparing fluoro ketone analogs as inhibitors of proteolytic enzymes [8][9][10] prompted us to report our work in this area. Here, we describe a series of small peptides containing a perfluoroalkyl ketone moiety incorporated at the Cterminal position of angiotensin I.…”

Section: Introductionmentioning

confidence: 99%

Highly potent and specific inhibitors of human renin

et al. 1987

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We have designed and synthesized a series of small peptides containing a perfluoroalkyl ketone group at the C‐terminal position of the angiotensin I sequence as inhibitors of human renin. From this series of compounds, 8 and 10 showed strong inhibition of human renin (IC50 = 3 × 10−9, 7 × 10−9 M, respectively). Compound 10 did not inhibit pepsin and cathepsin D at 10−4 M. Comparison of the IC50 of compound 8 and compound 11 (8.7 × 10−7 M) demonstrated the marked effect of the perfluoropropyl group on the potency of inhibition on renin, presumably due to the strong electron‐withdrawing effect causing the ketone in 8 to exist predominantly as the hydrate — thus mimicking the tetrahedral transition state during hydrolysis of the scissile Leu10—Val11 amide bond.

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Design and synthesis of potent and specific renin inhibitors containing difluorostatine, difluorostatone, and related analogs

Cited by 139 publications

References 4 publications

Inhibition of human immunodeficiency virus 1 protease in vitro: rational design of substrate analogue inhibitors.

Inhibition of human immunodeficiency virus 1 protease in vitro: rational design of substrate analogue inhibitors.

N-to-C Solid-Phase Peptide and Peptide Trifluoromethylketone Synthesis Using Amino Acid tert-Butyl Esters.

Highly potent and specific inhibitors of human renin

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