Discovery of a Peptide-Based Renin Inhibitor with Oral Bioavailability and Efficacy

Kleinert, Hollis D.; Rosenberg, Saul H.; Baker, William R.; Stein, Herman H.; Klinghofer, Vered; Barlow, Jennifer L.; Spina, Kenneth P.; Polakowski, James S.; Kovar, Peter; Cohen, Jerome; Denissen, Jon F.

doi:10.1126/science.1411510

Cited by 107 publications

(38 citation statements)

References 28 publications

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“…Through systematic studies of the relationship of structure to activity, pharmacokinetics, and metabolism, we have identified ABT-538, a peptidomimetic inhibitor of HIV protease with a unique combination of potency and oral bioavailability. In accord with recent reports of both renin (19) and HIV protease inhibitors (20) with promising pharmacokinetic properties, these results establish that peptidomimetic agents with high oral bioavailability in animals and humans can be discovered. As observed with another HIV protease inhibitor (21), the antiviral activity of ABT-538 in vivo is anticipated to be attenuated by .10-fold due to high (99%) binding to human plasma proteins.…”

Section: Resultssupporting

confidence: 87%

ABT-538 is a potent inhibitor of human immunodeficiency virus protease and has high oral bioavailability in humans.

Kempf

Marsh

Denissen

et al. 1995

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

519

327

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Examination of the structural basis for antiviral activity, oral pharmacokinetics, and hepatic metabolism among a series of symmetry-based inhibitors of the human immunodeficiency virus (HIV) protease led to the discovery of ABT-538, a promising experimental drug for the therapeutic intervention in acquired immunodeficiency syndrome (AIDS). ABT-538 exhibited potent in vitro activity against laboratory and clinical strains of HIV-1 [50%7 effective concentration (EC50) = 0.022-0.13 ,uM] and HIV-2 (EC50 = 0.16 ,uM). Following a single 10-mg/kg oral dose, plasma concentrations in rat, dog, and monkey exceeded the in vitro antiviral EC5. for > 12 h. In human trials, a single 400-mg dose of ABT-538 displayed a prolonged absorption profile and achieved a peak plasma concentration in excess of 5 ,ug/ml. These findings demonstrate that high oral bioavailability can be achieved in humans with peptidomimetic inhibitors of HIV protease.

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Section: Resultssupporting

confidence: 87%

ABT-538 is a potent inhibitor of human immunodeficiency virus protease and has high oral bioavailability in humans.

Kempf

Marsh

Denissen

et al. 1995

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

519

327

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“…Related phenyl vinyl sulfones also inhibit cruzain, a cysteine protease of Trypanosoma cruzi (31,32,35), and one of these compounds is currently undergoing preclinical studies for the treatment of Chagas' disease (34). While the clinical use of peptidyl protease inhibitors is potentially problematic due to limited bioavailability or poor pharmacokinetics, there are numerous recent reports of peptidyl inhibitors of renin (17), thrombin (11), leukocyte elastase (42), neutrophil elastase (8), and human immunodeficiency virus type 1 protease (2,16,40) that are biologically active after oral administration. Considering these data, the reported in vivo efficacy of an orally administered vinyl sulfone against murine malaria (22), and our demonstration here of marked antimalarial potency, additional evaluation of vinyl sulfonyl derivatives as potential antimalarial cysteine protease inhibitors seems appropriate.…”

Section: Discussionmentioning

confidence: 99%

Structure-Activity Relationships for Inhibition of Cysteine Protease Activity and Development of Plasmodium falciparum by Peptidyl Vinyl Sulfones

Shenai

Lee

Álvarez‐Hernández

et al. 2003

Antimicrob Agents Chemother

160

148

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The Plasmodium falciparum cysteine proteases falcipain-2 and falcipain-3 appear to be required for hemoglobin hydrolysis by intraerythrocytic malaria parasites. Previous studies showed that peptidyl vinyl sulfone inhibitors of falcipain-2 blocked the development of P. falciparum in culture and exerted antimalarial effects in vivo. We now report the structure-activity relationships for inhibition of falcipain-2, falcipain-3, and parasite development by 39 new vinyl sulfone, vinyl sulfonate ester, and vinyl sulfonamide cysteine protease inhibitors. Levels of inhibition of falcipain-2 and falcipain-3 were generally similar, and many potent compounds were identified. Optimal antimalarial compounds, which inhibited P. falciparum development at low nanomolar concentrations, were phenyl vinyl sulfones, vinyl sulfonate esters, and vinyl sulfonamides with P 2 leucine moieties. Our results identify independent structural correlates of falcipain inhibition and antiparasitic activity and suggest that peptidyl vinyl sulfones have promise as antimalarial agents.Malaria is one of the most important infectious diseases in the world. Plasmodium falciparum, the most virulent human malaria parasite, is estimated to cause over 300 million new cases and 1 million deaths annually (33). Further complicating this grim scenario is the emergence of the widespread resistance of P. falciparum to available antimalarial drugs (25). New drugs to combat malaria are urgently needed.Among potential new targets for antimalarial chemotherapy are enzymes that mediate hemoglobin hydrolysis. Intraerythrocytic P. falciparum trophozoites derive amino acids for protein synthesis from the hydrolysis of host cell hemoglobin in an acidic food vacuole (12,20,27). Proteases that hydrolyze hemoglobin in the food vacuole include members of the aspartic protease (1), cysteine protease (38, 39), and metalloprotease (9) families. Cysteine protease inhibitors arrested the erythrocytic life cycle of P. falciparum (26). Examination of inhibitortreated parasites revealed abnormally swollen food vacuoles filled with undigested hemoglobin, indicating that the block in parasite development was due to the inhibition of hemoglobin hydrolysis (26).P. falciparum contains three fairly typical papain family cysteine proteases, known as falcipains (28,38,39). Falcipain-2 and falcipain-3 appear to be the principal cysteine protease hemoglobinases (38, 39). Both of these proteases localize to vacuolar parasite fractions and readily hydrolyze hemoglobin under physiological reducing conditions at acidic pHs (37). Falcipain-2 is considerably more active against small peptide substrates, but the specificities of the two proteases are similar; both enzymes display a strong preference for leucine at the P 2 position (38, 39). The role of falcipain-1 in hemoglobin hydrolysis is unknown.In earlier studies, peptidyl vinyl sulfones inhibited falcipain-2 activity and parasite development at nanomolar concentrations and were active in vivo against murine malaria (22,29,30). We have now init...

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“…7]. The most successful concept to date is represented by transition-state substrate analogs [8] of the angiotensinogen-renin complex, with dipeptide cores or the equivalent [6,9,10], The crystal structure of renin has been reported [II]. Fig.…”

Section: Introductionmentioning

confidence: 99%

Hemodynamic Effects of Renin Inhibitors

Kleinert

1996

Am J Nephrol

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Renin inhibitors may offer an exciting new therapeutic means of blocking the actions of the renin-angiotensin-aldosterone system. These compounds interfere with the first, rate-limiting step in the synthesis of angiotensin II by binding directly to the highly specific enzyme, renin. This approach may represent a more focused alternative to angiotensin-converting enzyme inhibitor therapy with an improved side-effect profile. Renin inhibitors given parenterally safely lower blood pressure in patients with essential hypertension and improve the hemodynamic profile of patients with congestive heart failure. Under conditions of salt limitation, normal subjects show increases in renal plasma flow during infusion of renin inhibitors. The systemic and renal hemodynamic responses to renin inhibition are accompanied by suppression of plasma renin activity, plasma angiotensin II and plasma aldosterone levels. Recent scientific advances in discovering how to address the limitations of the low oral bioavailability of peptide-based compounds have made it possible to invent orally active renin inhibitors. Orally active renin inhibitors are presently being evaluated in clinical trials. The availability of intravenous and oral delivery of renin inhibitors broadens the potential of these agents to treat a wide variety of acute and chronic cardiorenal disorders.

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Discovery of a Peptide-Based Renin Inhibitor with Oral Bioavailability and Efficacy

Cited by 107 publications

References 28 publications

ABT-538 is a potent inhibitor of human immunodeficiency virus protease and has high oral bioavailability in humans.

ABT-538 is a potent inhibitor of human immunodeficiency virus protease and has high oral bioavailability in humans.

Structure-Activity Relationships for Inhibition of Cysteine Protease Activity and Development of Plasmodium falciparum by Peptidyl Vinyl Sulfones

Hemodynamic Effects of Renin Inhibitors

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