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

Peptidic renin inhibitors have been poorly absorbed across the intestine or rapidly eliminated by the liver and have been reported to have oral bioavailabilities of less than 2%. A peptide-based renin inhibitor, A-72517 (molecular mass of 706 daltons), was devised that has oral bioavailabilities of...

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Veröffentlicht in:Science (American Association for the Advancement of Science) 1992-09, Vol.257 (5078), p.1940-1943
Hauptverfasser: Kleinert, Hollis D., Rosenberg, Saul H., Baker, William R., Stein, Herman H., Klinghofer, Vered, Barlow, Jennifer, Spina, Kenneth, Polakowski, James, Kovar, Peter, Cohen, Jerome, Denissen, Jon
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container_end_page 1943
container_issue 5078
container_start_page 1940
container_title Science (American Association for the Advancement of Science)
container_volume 257
creator Kleinert, Hollis D.
Rosenberg, Saul H.
Baker, William R.
Stein, Herman H.
Klinghofer, Vered
Barlow, Jennifer
Spina, Kenneth
Polakowski, James
Kovar, Peter
Cohen, Jerome
Denissen, Jon
description Peptidic renin inhibitors have been poorly absorbed across the intestine or rapidly eliminated by the liver and have been reported to have oral bioavailabilities of less than 2%. A peptide-based renin inhibitor, A-72517 (molecular mass of 706 daltons), was devised that has oral bioavailabilities of 8, 24, 32, and 53% in the monkey, rat, ferret, and dog, respectively. Dose-related reductions in blood pressure, plasma renin activity, and plasma angiotensin II in parallel with increased plasma drug concentrations were observed after oral administration of A-72517 to conscious, salt-depleted dogs. Thus, peptide-based molecules of sizable molecular mass can be absorbed intact into the systemic circulation of animals. These findings support the potential of peptide-based drugs for oral administration.
doi_str_mv 10.1126/science.1411510
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A peptide-based renin inhibitor, A-72517 (molecular mass of 706 daltons), was devised that has oral bioavailabilities of 8, 24, 32, and 53% in the monkey, rat, ferret, and dog, respectively. Dose-related reductions in blood pressure, plasma renin activity, and plasma angiotensin II in parallel with increased plasma drug concentrations were observed after oral administration of A-72517 to conscious, salt-depleted dogs. Thus, peptide-based molecules of sizable molecular mass can be absorbed intact into the systemic circulation of animals. 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Drug treatments</subject><subject>Physiological aspects</subject><subject>Piperazines - chemistry</subject><subject>Piperazines - pharmacokinetics</subject><subject>Piperazines - pharmacology</subject><subject>Protease Inhibitors - chemistry</subject><subject>Protease Inhibitors - metabolism</subject><subject>Protease Inhibitors - pharmacokinetics</subject><subject>Rats</subject><subject>renin</subject><subject>Renin - antagonists &amp; inhibitors</subject><subject>Renin-angiotensin system</subject><subject>Structure-Activity Relationship</subject><subject>Thiazoles - chemistry</subject><subject>Thiazoles - pharmacokinetics</subject><subject>Thiazoles - pharmacology</subject><subject>Vehicles</subject><issn>0036-8075</issn><issn>1095-9203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1992</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqN0kFv0zAUB3ALgcYYnLmA5ANCHJbNL07i5LiWUSpVFDHgGr04z52nNCl2Oui3x1WjokqVqHOwlPeL9Zz3Z-w1iCuAOLv22lKr6QoSgBTEE3YOokijIhbyKTsXQmZRLlT6nL3w_kGIUCvkGTsb-Dm7-2i97h7JbXhnOPKvtOptTdEIPdX8G7W25dP23la27xz_bft7PnfY8JHt8BFtg5VtbL_h2Nb81hirUW9esmcGG0-vhv2C_fh0-338OZrNJ9PxzSzSWZL3kTQJ6AqxAJmHpaq6Nkmh09zEKLCIEVSiZEaFSoEMxLLSKSR1lqVZZuIqkRfs_e7clet-rcn35TJchpoGW-rWvlQyVgBF-l8ImYQ8dBHg5Q4usKHStqbrHeoFtRTu3LVkbHh9E_67gkJsG4iO8PDUtLT6mP9w4APp6U-_wLX35fTuy8l0_vNkOpqcSvPJ7IBeHqO6axpaUBkGOZ4f8Osd167z3pEpV84u0W1KEOU2qeWQ1HKIXvji7TCUdbWk-p_f198NdfQaG-Ow1dbvWSKFVMl2ZG927MGHhO7Lca6KPMT_Lz_P9QA</recordid><startdate>19920925</startdate><enddate>19920925</enddate><creator>Kleinert, Hollis D.</creator><creator>Rosenberg, Saul H.</creator><creator>Baker, William R.</creator><creator>Stein, Herman H.</creator><creator>Klinghofer, Vered</creator><creator>Barlow, Jennifer</creator><creator>Spina, Kenneth</creator><creator>Polakowski, James</creator><creator>Kovar, Peter</creator><creator>Cohen, Jerome</creator><creator>Denissen, Jon</creator><general>American Society for the Advancement of Science</general><general>American Association for the Advancement of Science</general><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>8GL</scope><scope>IBG</scope><scope>IOV</scope><scope>ISN</scope><scope>7QL</scope><scope>7QO</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>M81</scope><scope>P64</scope><scope>7X8</scope></search><sort><creationdate>19920925</creationdate><title>Discovery of a Peptide-Based Renin Inhibitor with Oral Bioavailability and Efficacy</title><author>Kleinert, Hollis D. ; Rosenberg, Saul H. ; Baker, William R. ; Stein, Herman H. ; Klinghofer, Vered ; Barlow, Jennifer ; Spina, Kenneth ; Polakowski, James ; Kovar, Peter ; Cohen, Jerome ; Denissen, Jon</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c648t-3f41cbaa91388887bddf49c58f2a0a92a174736e9751ef123bc514d66566f2b43</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1992</creationdate><topic>administration</topic><topic>Administration, Oral</topic><topic>Animals</topic><topic>Antihypertensive agents</topic><topic>Bioavailability</topic><topic>Biological and medical sciences</topic><topic>Biological Availability</topic><topic>Blood</topic><topic>Blood plasma</topic><topic>Blood pressure</topic><topic>Cardiovascular agents</topic><topic>Cardiovascular system</topic><topic>Dogs</topic><topic>Dosage</topic><topic>efficacy</topic><topic>Ferrets</topic><topic>Health aspects</topic><topic>Hemodynamics - drug effects</topic><topic>inhibitors</topic><topic>Medical sciences</topic><topic>Monkeys</topic><topic>Peptides</topic><topic>Pharmacology. Drug treatments</topic><topic>Physiological aspects</topic><topic>Piperazines - chemistry</topic><topic>Piperazines - pharmacokinetics</topic><topic>Piperazines - pharmacology</topic><topic>Protease Inhibitors - chemistry</topic><topic>Protease Inhibitors - metabolism</topic><topic>Protease Inhibitors - pharmacokinetics</topic><topic>Rats</topic><topic>renin</topic><topic>Renin - antagonists &amp; inhibitors</topic><topic>Renin-angiotensin system</topic><topic>Structure-Activity Relationship</topic><topic>Thiazoles - chemistry</topic><topic>Thiazoles - pharmacokinetics</topic><topic>Thiazoles - pharmacology</topic><topic>Vehicles</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Kleinert, Hollis D.</creatorcontrib><creatorcontrib>Rosenberg, Saul H.</creatorcontrib><creatorcontrib>Baker, William R.</creatorcontrib><creatorcontrib>Stein, Herman H.</creatorcontrib><creatorcontrib>Klinghofer, Vered</creatorcontrib><creatorcontrib>Barlow, Jennifer</creatorcontrib><creatorcontrib>Spina, Kenneth</creatorcontrib><creatorcontrib>Polakowski, James</creatorcontrib><creatorcontrib>Kovar, Peter</creatorcontrib><creatorcontrib>Cohen, Jerome</creatorcontrib><creatorcontrib>Denissen, Jon</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Gale In Context: High School</collection><collection>Gale In Context: Biography</collection><collection>Gale In Context: Opposing Viewpoints</collection><collection>Gale In Context: Canada</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Biotechnology Research Abstracts</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Engineering Research Database</collection><collection>Biochemistry Abstracts 3</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Science (American Association for the Advancement of Science)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Kleinert, Hollis D.</au><au>Rosenberg, Saul H.</au><au>Baker, William R.</au><au>Stein, Herman H.</au><au>Klinghofer, Vered</au><au>Barlow, Jennifer</au><au>Spina, Kenneth</au><au>Polakowski, James</au><au>Kovar, Peter</au><au>Cohen, Jerome</au><au>Denissen, Jon</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Discovery of a Peptide-Based Renin Inhibitor with Oral Bioavailability and Efficacy</atitle><jtitle>Science (American Association for the Advancement of Science)</jtitle><addtitle>Science</addtitle><date>1992-09-25</date><risdate>1992</risdate><volume>257</volume><issue>5078</issue><spage>1940</spage><epage>1943</epage><pages>1940-1943</pages><issn>0036-8075</issn><eissn>1095-9203</eissn><coden>SCIEAS</coden><abstract>Peptidic renin inhibitors have been poorly absorbed across the intestine or rapidly eliminated by the liver and have been reported to have oral bioavailabilities of less than 2%. A peptide-based renin inhibitor, A-72517 (molecular mass of 706 daltons), was devised that has oral bioavailabilities of 8, 24, 32, and 53% in the monkey, rat, ferret, and dog, respectively. Dose-related reductions in blood pressure, plasma renin activity, and plasma angiotensin II in parallel with increased plasma drug concentrations were observed after oral administration of A-72517 to conscious, salt-depleted dogs. Thus, peptide-based molecules of sizable molecular mass can be absorbed intact into the systemic circulation of animals. These findings support the potential of peptide-based drugs for oral administration.</abstract><cop>Washington, DC</cop><pub>American Society for the Advancement of Science</pub><pmid>1411510</pmid><doi>10.1126/science.1411510</doi><tpages>4</tpages></addata></record>
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source MEDLINE; Science Magazine; Jstor Complete Legacy
subjects administration
Administration, Oral
Animals
Antihypertensive agents
Bioavailability
Biological and medical sciences
Biological Availability
Blood
Blood plasma
Blood pressure
Cardiovascular agents
Cardiovascular system
Dogs
Dosage
efficacy
Ferrets
Health aspects
Hemodynamics - drug effects
inhibitors
Medical sciences
Monkeys
Peptides
Pharmacology. Drug treatments
Physiological aspects
Piperazines - chemistry
Piperazines - pharmacokinetics
Piperazines - pharmacology
Protease Inhibitors - chemistry
Protease Inhibitors - metabolism
Protease Inhibitors - pharmacokinetics
Rats
renin
Renin - antagonists & inhibitors
Renin-angiotensin system
Structure-Activity Relationship
Thiazoles - chemistry
Thiazoles - pharmacokinetics
Thiazoles - pharmacology
Vehicles
title Discovery of a Peptide-Based Renin Inhibitor with Oral Bioavailability and Efficacy
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