Active site-directed thrombin inhibitors: α-hydroxyacylprolyl-arginals. New orally active stable analogs of d-Phe-Pro-Arg-H

Bajusz, S.; Barabás, Éva; Fauszt, I; Fehér, A.; Horváth, Gy.; Juhász, Attila; Szabó, A.G.; Széll, E.

doi:10.1016/0968-0896(95)00108-s

Cited by 8 publications

(2 citation statements)

References 14 publications

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“…To examine their P3 structural preferences, granzymes A and K, mast cell tryptase, and trypsin were investigated with analogues of RCO-AA-Ala- d , l -(4-AmPhGly) P (OPh) 2 . Several N-blocked-Pro-(4-AmPhGly) P (OPh) 2 analogues that were developed as thrombin inhibitors based on current literature − were found to be excellent inhibitors for the enzymes in this study. The derivative Ph-CH 2 -SO 2 -Gly-Pro-(4-AmPhGly) P (OPh) 2 ( 43 ) was the most potent of this series against granzyme A ( k obs /[I] = 3650 M -1 s -1 ).…”

Section: Resultsmentioning

confidence: 83%

Synthesis and Evaluation of Diphenyl Phosphonate Esters as Inhibitors of the Trypsin-like Granzymes A and K and Mast Cell Tryptase

Jackson

Fraser

et al. 1998

J. Med. Chem.

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Thirty-six new amino acid and peptidyl diphenyl phosphonate esters were synthesized and evaluated to identify potent and selective inhibitors for four trypsin-like proteases: lymphocyte granzymes A and K, human mast cell tryptase, and pancreatic trypsin. Among five Cbz derivatives of Lys and Arg homologues, Z-(4-AmPhe)P(OPh)2 is the most potent inhibitor for granzyme A, and Z-LysP(OPh)2 is the best inhibitor for granzyme K, mast tryptase, and trypsin. The amidino P1 residue D,L-(4-AmPhGly)P(OPh)2 was utilized in a series of compounds with several different N-protecting groups and systematic substitutions at P2 in Cbz-AA derivatives and at P3 in Cbz-AA-Ala derivatives. Generally, these phosphonates inhibit granzyme A and trypsin more potently than granzyme K and tryptase. The P2 Thr and Ala dipeptide phosphonates, Cbz-AA-(4-AmPhGly)P(OPh)2, are the most potent inhibitors for granzyme A, and Cbz-Thr-(4-AmPhGly)P(OPh)2 (kobs/[I] = 2220 M-1 s-1) was quite specific with much lower inhibition rates for granzyme K and trypsin (kobs/[I] = 3 and 97 M-1 s-1, respectively) and no inhibition with tryptase. The most effective inhibitor of granzyme A was Ph-SO2-Gly-Pro-(4-AmPhGly)P(OPh)2 with a second-order rate constant of 3650 M-1 s-1. The most potent inhibitor for granzyme K was 3, 3-diphenylpropanoyl-Pro-(4-AmPhGly)P(OPh)2 with a kobs/[I] = 1830 M-1 s-1; all other phosphonates inhibited granzyme K weakly (kobs/[I] < 60 M-1 s-1). Human mast cell tryptase was inhibited slowly by these phosphonates with Cbz-LysP(OPh)2 as the best inhibitor (kobs/[I] = 89 M-1 s-1). The overall results suggest that scaffolds of Phe-Thr-(4-AmPhe) and Phe-Pro-Lys will be useful to create selective phosphonate inhibitors for granzymes A and K, respectively, and that P4 substituents offer opportunities to further enhance selectivity and reactivity.

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Section: Resultsmentioning

confidence: 83%

Synthesis and Evaluation of Diphenyl Phosphonate Esters as Inhibitors of the Trypsin-like Granzymes A and K and Mast Cell Tryptase

Jackson

Fraser

et al. 1998

J. Med. Chem.

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“…Thrombin inhibitors are important agents in treating or preventing thrombosis disorders. Many thrombin inhibitors have been designed and synthesized in recent years. − Substrate analogue strategy has been used in the design of reversible thrombin inhibitor d -Phe-Pro-Argininal ( 1 ) and the irreversible potent inhibitor chromethyl ketone d -Phe-Pro-ArgCH 2 Cl ( 2 ) (PPACK) . These compounds and the crystal structures of thrombin complexes with inhibitors including PPACK were often used as the starting point for structure optimizations of novel thrombin inhibitors. , Conformational restricted inhibitors that can preorganize into optimal conformations for the binding site are potentially more selective and could have better therapeutic profiles.…”

Section: Introductionmentioning

confidence: 99%

Synthesis of a Ring-Oxygenated Variant of the 2-Carboxy-6-hydroxyoctahydroindole Core of Aeruginosin 298-A from Glucose

Nie

Wang

2005

J. Org. Chem.

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[reaction: see text] The design and synthesis of a new core structure, a ring-oxygenated variant of 2-carboxy-6-hydroxyoctahydroindole (Choi) from D-glucose, is reported. Choi, a rigid bicyclic unnatural amino acid, is the core structure of about 15 aeruginosins natural compounds. These compounds are thrombin, trypsin, and factor VIIa inhibitors and Choi is important for their biological activity. The ring-oxygenated variant of 2-carboxy-6-hydroxyoctahydroindole can potentially be used as a surrogate of Choi in the design and synthesis of aeruginosin-based thrombin inhibitors.

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Peptide related drug research

Bajusz¹

2003

Journal of Peptide Science

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Drug discovery directed peptide research has been pursued at the IVAX Drug Research Institute (formerly Institute for Drug Research) (IDR) since the mid 1950s. Outlined are the main projects and the most significant results, which include the first synthesis of human ACTH, the discovery of GYKI-14 166, the prototype of peptide inhibitors of thrombin, a stable anticoagulant, efegatran GYKI-14 766, and their dual acting analogues. The identification of an agonist analogue of LHRH leading to Cetrorelix, an LHRH antagonist now in clinical use, is also presented.

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Active site-directed thrombin inhibitors: α-hydroxyacylprolyl-arginals. New orally active stable analogs of d-Phe-Pro-Arg-H

Cited by 8 publications

References 14 publications

Synthesis and Evaluation of Diphenyl Phosphonate Esters as Inhibitors of the Trypsin-like Granzymes A and K and Mast Cell Tryptase

Synthesis and Evaluation of Diphenyl Phosphonate Esters as Inhibitors of the Trypsin-like Granzymes A and K and Mast Cell Tryptase

Synthesis of a Ring-Oxygenated Variant of the 2-Carboxy-6-hydroxyoctahydroindole Core of Aeruginosin 298-A from Glucose

Peptide related drug research

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