Development of an Orally Active Tripeptide Arginal Thrombin Inhibitor

Shuman, Robert T.; Gesellchen, Paul D.

doi:10.1007/0-306-47384-4_4

Cited by 3 publications

(2 citation statements)

References 21 publications

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“…The thrombin inhibitory activity and in vitro anticoagulant profile of 23c , 28c , and 31c were compared to the tripeptide arginal, R -1-Piq-Pro-Arg-H (H- R -1-[4a S ,8a S ]-perhydroisoquinolyl-prolyl-arginyl aldehyde; 32 ), to assess the significance of the novel compounds from this study. This potent tripeptide thrombin inhibitor entered phase I clinical trials as an oral anticoagulant candidate, and therefore, its in vitro activity could serve as a benchmark for the current work.…”

Section: Resultsmentioning

confidence: 99%

Diamino Benzo[b]thiophene Derivatives as a Novel Class of Active Site Directed Thrombin Inhibitors. 5. Potency, Efficacy, and Pharmacokinetic Properties of Modified C-3 Side Chain Derivatives

et al. 2000

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A systematic investigation of the structure-activity relationships of the C-3 side chain of the screening hit 1a led to the identification of the potent thrombin inhibitors 23c, 28c, and 31c. Their activities (1240, 903, and 1271 x 10(6) L/mol, respectively) represent 2200- and 2900-fold increases in potency over the starting lead 1a. This activity enhancement was accomplished with an increase of thrombin selectivity. The in vitro anticoagulant profiles of derivatives 28c and 31c were determined, and they compare favorably with the clinical agent H-R-1-[4aS, 8aS]perhydroisoquinolyl-prolyl-arginyl aldehyde (D-Piq-Pro-Arg-H; 32). The more potent members of this series have been studied in an arterial/venous shunt (AV shunt) model of thrombosis and were found to be efficacious in reducing clot formation. However, their efficacy is currently limited by their rapid and extensive distribution following administration.

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Section: Resultsmentioning

confidence: 99%

Diamino Benzo[b]thiophene Derivatives as a Novel Class of Active Site Directed Thrombin Inhibitors. 5. Potency, Efficacy, and Pharmacokinetic Properties of Modified C-3 Side Chain Derivatives

et al. 2000

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“…S-18326 with a relatively higher activity to trypsin than S-31922 exhibited more food effect. Another example, R-Piq-Pro-Arg-H (Eli Lilly Co.), is also well absorbed when administered orally on an empty stomach, but its bioavailability decreases remarkably in rats and human subjects in fed state . Although its activity to trypsin has not been reported, an arginine derivative with a molecular structure similar to that of S-18326 described above is likely to have a high activity to trypsin.…”

Section: Discussionmentioning

confidence: 99%

A Food Effect Study of an Oral Thrombin Inhibitor and Prodrug Approach To Mitigate It

Lee

Kim²,

Kim³

et al. 2016

Mol. Pharmaceutics

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LB30870, a new direct thrombin inhibitor, showed 80% reduction in oral bioavailability in fed state. The present study aims to propose trypsin binding as a mechanism for such negative food effect and demonstrate a prodrug approach to mitigate food effect. Effect of food composition on fed state oral bioavailability of LB30870 was studied in dogs. Various prodrugs were synthesized, and their solubility, permeability, and trypsin binding affinity were measured. LB30870 and prodrugs were subject to cocrystallization with trypsin, and the X-ray structures of cocrystals were determined. Food effect was studied in dogs for selected prodrugs. Protein or lipid meal appeared to affect oral bioavailability of LB30870 in dogs more than carbohydrate meal. Blocking both carboxyl and amidine groups of LB30870 resulted in trypsin Ki values orders of magnitude higher than that of LB30870. Prodrugs belonged to either Biopharmaceutical Classification System I, II, or III. X-ray crystallography revealed that prodrugs did not bind to trypsin, but instead their hydrolysis product at the amidine blocking group formed cocrystal with trypsin. A prodrug with significantly less food effect than LB30870 was identified. Binding of prodrugs to food components such as dietary fiber appeared to counteract the positive effect brought with the prodrug approach. Further formulation research is warranted to enhance the oral bioavailability of prodrugs. In conclusion, this study is the first to demonstrate that the negative food effect of LB30870 can be attributed to trypsin binding. Trypsin binding study is proposed as a screening tool during lead optimization to minimize food effect.

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Antithrombotic drugs

Hemker¹,

Giesen²,

Wagenvoord³

et al. 1999

Emerging Drugs

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Development of an Orally Active Tripeptide Arginal Thrombin Inhibitor

Cited by 3 publications

References 21 publications

Diamino Benzo[b]thiophene Derivatives as a Novel Class of Active Site Directed Thrombin Inhibitors. 5. Potency, Efficacy, and Pharmacokinetic Properties of Modified C-3 Side Chain Derivatives

Diamino Benzo[b]thiophene Derivatives as a Novel Class of Active Site Directed Thrombin Inhibitors. 5. Potency, Efficacy, and Pharmacokinetic Properties of Modified C-3 Side Chain Derivatives

A Food Effect Study of an Oral Thrombin Inhibitor and Prodrug Approach To Mitigate It

Antithrombotic drugs

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