Amide and α-keto carbonyl inhibitors of thrombin based on arginine and lysine: Synthesis, stability and biological characterization

Brady, Susan; Sisko, John T.; Stauffer, Kenneth J.; Colton, C. D.; Qiu, Howard; Lewis, Sidney D.; Ng, Assunta S.; Shafer, Jules A.; Bogusky, Michael J.; Veber, Daniel F.; Nutt, Ruth F.

doi:10.1016/0968-0896(95)00105-p

Cited by 34 publications

(27 citation statements)

References 17 publications

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“…r-Hirudin was produced in Saccharomyces cerevisiae as previously described (16). Syntheses of the amide and a-keto carbonyl derivatives of H (or H-N-Me)-D-Phe-Pro-Lys have been reported elsewhere (15). Inhibitors were stored and diluted in 1 mM HCI before final addition into buffer.…”

Section: Methodsmentioning

confidence: 99%

“…H-N-Me-D-Phe-Pro-Lysyl-carboxamides, -carboxylic acid and -carboxyethyl ester are slow-binding thrombin inhibitors, and therefore require prolon ged incubation with target proteinases to achieve equilibration (7,15). Values of K; were determine using methods previously described for the slow-binding thrombin inhibitor CyA (7).…”

Section: Determination O F Inhibition Constants (K)mentioning

confidence: 99%

“…Iwanowicz et al reported that an a-keto ester-containing deri vative of H-D-Phe-Pro-Lys (BMS 181,412) was a potent thrombin inhibitor (14). A drawback of a-keto esters is that they are relatively unstable in buffers at physiological pH (15).…”

Section: Introductionmentioning

confidence: 99%

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Inhibition of Thrombin by Peptides Containing Lysyl-α-Keto Carbonyl Derivatives

et al. 1995

Thromb Haemost

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SummarySeveral H-N-Me-D-Phe-Pro-Lysyl-α-keto carbonyl derivatives were shown to be potent thrombin inhibitors (Ki 0.2 to 27 nM). The inhibitory potencies of these compounds toward tissue plasminogen activator, plasmin and factor Xa were minimal; however, substantial cross-reactivity versus trypsin was observed (Ki values from 0.5 to 1500 nM). Inhibition of thrombin by α-keto carbonyl compounds appeared to occur via a one-step reversible reaction. The α-keto carbonyl inhibitors bound thrombin with a second order rate constant (k, 1–4 μM-1s-1) that was 10–100-fold slower than that expected for a diffusion-controlled reaction. Certain α-kelo earbonyl inhibitors were as potent (on a weight basis) as hirudin when evaluated in a rat arterial thrombosis model. The modest oral bioavailability (10–19%) in rats demonstrated for three of the α-keto carbonyl thrombin inhibitors suggests the possibility that α-keto amide containing thrombin inhibitors may have utility as orally-active antithrombotic agents.

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Section: Methodsmentioning

confidence: 99%

Section: Determination O F Inhibition Constants (K)mentioning

confidence: 99%

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Inhibition of Thrombin by Peptides Containing Lysyl-α-Keto Carbonyl Derivatives

et al. 1995

Thromb Haemost

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“…This work culminated in the synthesis of potent ␣-ketoamide L-370,518 (20) (thrombin Ki ϭ 0.09 nM, bovine trypsin Ki ϭ 1,150 nM). 62 The issues of synthetic difficulty, 63 stability and potential toxicity prompted Lyle et al to delete the ketoamide serine trap of this compound. 64 Unexpectedly the resulting compound L-371,912 (21) (Ki ϭ 5 nM) was only 50-fold less potent than L-370,518.…”

Section: B Thrombin Inhibitors Originating From the Tripeptide Arginmentioning

confidence: 99%

Small, noncovalent serine protease inhibitors

Sanderson

1999

Med. Res. Rev.

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“…A critical inadequacy is the lack of suitable protecting groups for α -ketoacids. Common strategies such as protection as esters or amides promote epimerization or accentuate the electrophilic properties of the ketone 7. In this report, we disclose an unexpectedly simple strategy for the chemoselective protection of α -ketoacids via direct annulations with oximes (eq 1).…”

mentioning

confidence: 97%

Chemoselective Protection of α-Ketoacids by Direct Annulations with Oximes

Flores

Bode

2010

Org. Lett.

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Oximes and α-ketoacids undergo an unexpectedly facile and chemoselective annulation to afford 2,5-dihydrooxazole 3-oxides. The resulting cyclic nitrones serve as chemically and configurationally stable masked α-ketoacids that can be easily elaborated and manipulated. Deprotection is achieved by mild reduction with zinc metal and hydrolysis. This methodology allows for the protection, elaboration, and deprotection of enantiopure peptide derived α-ketoacids, which are the key starting materials for the chemoselective ketoacid–hydroxylamine peptide ligation.

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Amide and α-keto carbonyl inhibitors of thrombin based on arginine and lysine: Synthesis, stability and biological characterization

Cited by 34 publications

References 17 publications

Inhibition of Thrombin by Peptides Containing Lysyl-α-Keto Carbonyl Derivatives

Inhibition of Thrombin by Peptides Containing Lysyl-α-Keto Carbonyl Derivatives

Small, noncovalent serine protease inhibitors

Chemoselective Protection of α-Ketoacids by Direct Annulations with Oximes

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