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 |
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container_end_page | 1943 |
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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 |
format | Article |
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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. These findings support the potential of peptide-based drugs for oral administration.</description><identifier>ISSN: 0036-8075</identifier><identifier>EISSN: 1095-9203</identifier><identifier>DOI: 10.1126/science.1411510</identifier><identifier>PMID: 1411510</identifier><identifier>CODEN: SCIEAS</identifier><language>eng</language><publisher>Washington, DC: American Society for the Advancement of Science</publisher><subject>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</subject><ispartof>Science (American Association for the Advancement of Science), 1992-09, Vol.257 (5078), p.1940-1943</ispartof><rights>Copyright 1992 American Association for the Advancement of Science</rights><rights>1993 INIST-CNRS</rights><rights>COPYRIGHT 1992 American Association for the Advancement of Science</rights><rights>COPYRIGHT 1992 American Association for the Advancement of Science</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c648t-3f41cbaa91388887bddf49c58f2a0a92a174736e9751ef123bc514d66566f2b43</citedby><cites>FETCH-LOGICAL-c648t-3f41cbaa91388887bddf49c58f2a0a92a174736e9751ef123bc514d66566f2b43</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.jstor.org/stable/pdf/2879800$$EPDF$$P50$$Gjstor$$H</linktopdf><linktohtml>$$Uhttps://www.jstor.org/stable/2879800$$EHTML$$P50$$Gjstor$$H</linktohtml><link.rule.ids>314,777,781,800,2871,2872,27905,27906,57998,58231</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=4303748$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/1411510$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><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><title>Discovery of a Peptide-Based Renin Inhibitor with Oral Bioavailability and Efficacy</title><title>Science (American Association for the Advancement of Science)</title><addtitle>Science</addtitle><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.</description><subject>administration</subject><subject>Administration, Oral</subject><subject>Animals</subject><subject>Antihypertensive agents</subject><subject>Bioavailability</subject><subject>Biological and medical sciences</subject><subject>Biological Availability</subject><subject>Blood</subject><subject>Blood plasma</subject><subject>Blood pressure</subject><subject>Cardiovascular agents</subject><subject>Cardiovascular system</subject><subject>Dogs</subject><subject>Dosage</subject><subject>efficacy</subject><subject>Ferrets</subject><subject>Health aspects</subject><subject>Hemodynamics - drug effects</subject><subject>inhibitors</subject><subject>Medical sciences</subject><subject>Monkeys</subject><subject>Peptides</subject><subject>Pharmacology. 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 & 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 & 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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