5 -(3 -Cyclopentyl -2 -thioxo -2,3 -dihydro -1H -benzimidazol -5 -yl )-1-methyl -1H-pyrrole -2 -carbonitrile : A novel, highly potent, selective, and orally active non-steroidal progesterone receptor agonist
We have recently discovered 5-(3-cyclopentyl-2-thioxo-2,3-dihydro-1H-benzimidazol-5-yl)-1-methyl-1H-pyrrole-2-carbonitrile (14) as a potent, selective, and orally active non-steroidal progesterone receptor (PR) agonist. Compound 14 and its analog 13 possessed sub-nanomolar in vitro potency (EC(50) 0...
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| Veröffentlicht in: | Bioorganic & medicinal chemistry 2007-10, Vol.15 (20), p.6556-6564 |
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| creator | PUWEN ZHANG TEREFENKO, Eugene LACAVA, Margaret WINNEKER, Richard C ZHIMING ZHANG KERN, Jeffrey FENSOME, Andrew TRYBULSKI, Eugene UNWALLA, Ray WROBEL, Jay LOCKHEAD, Susan YUAN ZHU COHEN, Jeffrey |
| description | We have recently discovered 5-(3-cyclopentyl-2-thioxo-2,3-dihydro-1H-benzimidazol-5-yl)-1-methyl-1H-pyrrole-2-carbonitrile (14) as a potent, selective, and orally active non-steroidal progesterone receptor (PR) agonist. Compound 14 and its analog 13 possessed sub-nanomolar in vitro potency (EC(50) 0.1-0.5nM) in the T47D alkaline phosphatase assay, similar to that of the steroidal PR agonist medroxyprogesterone acetate (MPA). In contrast to MPA, 14 was highly selective (>500-fold) for the PR over both glucocorticoid and androgen receptors. In the rat uterine decidualization and complement component C3 models, 14 had oral ED(50) values of 0.02 and 0.003mg/kg, respectively, and was from 6- to 20-fold more potent than MPA. In the monkey ovulation inhibition model, compound 14 was also highly efficacious and potent with an oral ED(100) of 0.03mg/kg. |
| doi_str_mv | 10.1016/j.bmc.2007.07.011 |
| format | Article |
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Compound 14 and its analog 13 possessed sub-nanomolar in vitro potency (EC(50) 0.1-0.5nM) in the T47D alkaline phosphatase assay, similar to that of the steroidal PR agonist medroxyprogesterone acetate (MPA). In contrast to MPA, 14 was highly selective (>500-fold) for the PR over both glucocorticoid and androgen receptors. In the rat uterine decidualization and complement component C3 models, 14 had oral ED(50) values of 0.02 and 0.003mg/kg, respectively, and was from 6- to 20-fold more potent than MPA. In the monkey ovulation inhibition model, compound 14 was also highly efficacious and potent with an oral ED(100) of 0.03mg/kg.</description><identifier>ISSN: 0968-0896</identifier><identifier>EISSN: 1464-3391</identifier><identifier>DOI: 10.1016/j.bmc.2007.07.011</identifier><identifier>PMID: 17681796</identifier><language>eng</language><publisher>Oxford: Elsevier Science</publisher><subject>Administration, Oral ; Alkaline Phosphatase - metabolism ; Animals ; Biological and medical sciences ; Cell Line, Tumor ; Female ; Hormones. Endocrine system ; Medical sciences ; Models, Molecular ; Molecular Structure ; Nitriles - chemistry ; Nitriles - pharmacology ; Pharmacology. Drug treatments ; Pyrroles - chemistry ; Pyrroles - pharmacology ; Rats ; Rats, Sprague-Dawley ; Receptors, Progesterone - agonists ; Receptors, Progesterone - metabolism ; Steroids - chemistry ; Steroids - pharmacology</subject><ispartof>Bioorganic & medicinal chemistry, 2007-10, Vol.15 (20), p.6556-6564</ispartof><rights>2008 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c354t-d500cf03ec10f9e62246e76b579a32c8b2f85df48e2be6e034d1db01f6b062a63</citedby><cites>FETCH-LOGICAL-c354t-d500cf03ec10f9e62246e76b579a32c8b2f85df48e2be6e034d1db01f6b062a63</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27924,27925</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=19042577$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/17681796$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>PUWEN ZHANG</creatorcontrib><creatorcontrib>TEREFENKO, Eugene</creatorcontrib><creatorcontrib>LACAVA, Margaret</creatorcontrib><creatorcontrib>WINNEKER, Richard C</creatorcontrib><creatorcontrib>ZHIMING ZHANG</creatorcontrib><creatorcontrib>KERN, Jeffrey</creatorcontrib><creatorcontrib>FENSOME, Andrew</creatorcontrib><creatorcontrib>TRYBULSKI, Eugene</creatorcontrib><creatorcontrib>UNWALLA, Ray</creatorcontrib><creatorcontrib>WROBEL, Jay</creatorcontrib><creatorcontrib>LOCKHEAD, Susan</creatorcontrib><creatorcontrib>YUAN ZHU</creatorcontrib><creatorcontrib>COHEN, Jeffrey</creatorcontrib><title>5 -(3 -Cyclopentyl -2 -thioxo -2,3 -dihydro -1H -benzimidazol -5 -yl )-1-methyl -1H-pyrrole -2 -carbonitrile : A novel, highly potent, selective, and orally active non-steroidal progesterone receptor agonist</title><title>Bioorganic & medicinal chemistry</title><addtitle>Bioorg Med Chem</addtitle><description>We have recently discovered 5-(3-cyclopentyl-2-thioxo-2,3-dihydro-1H-benzimidazol-5-yl)-1-methyl-1H-pyrrole-2-carbonitrile (14) as a potent, selective, and orally active non-steroidal progesterone receptor (PR) agonist. Compound 14 and its analog 13 possessed sub-nanomolar in vitro potency (EC(50) 0.1-0.5nM) in the T47D alkaline phosphatase assay, similar to that of the steroidal PR agonist medroxyprogesterone acetate (MPA). In contrast to MPA, 14 was highly selective (>500-fold) for the PR over both glucocorticoid and androgen receptors. In the rat uterine decidualization and complement component C3 models, 14 had oral ED(50) values of 0.02 and 0.003mg/kg, respectively, and was from 6- to 20-fold more potent than MPA. In the monkey ovulation inhibition model, compound 14 was also highly efficacious and potent with an oral ED(100) of 0.03mg/kg.</description><subject>Administration, Oral</subject><subject>Alkaline Phosphatase - metabolism</subject><subject>Animals</subject><subject>Biological and medical sciences</subject><subject>Cell Line, Tumor</subject><subject>Female</subject><subject>Hormones. Endocrine system</subject><subject>Medical sciences</subject><subject>Models, Molecular</subject><subject>Molecular Structure</subject><subject>Nitriles - chemistry</subject><subject>Nitriles - pharmacology</subject><subject>Pharmacology. Drug treatments</subject><subject>Pyrroles - chemistry</subject><subject>Pyrroles - pharmacology</subject><subject>Rats</subject><subject>Rats, Sprague-Dawley</subject><subject>Receptors, Progesterone - agonists</subject><subject>Receptors, Progesterone - metabolism</subject><subject>Steroids - chemistry</subject><subject>Steroids - pharmacology</subject><issn>0968-0896</issn><issn>1464-3391</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2007</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpFUV-L1DAQD6J4e6cfwBfJi3LCZs2kbdr6dizqCge-6HNJ0-lulrSpSfaw9yX9SqZ7CwcDycz8_gz8CHkHfAMc5Ofjph30RnBebpYCeEFWkMucZVkNL8mK17JivKrlFbkO4cg5F3kNr8kVlLKCspYr8q-g7DajbDtr6yYc42wpE5TFg3F_Xfqu07Izh7nzqYMdZS2Oj2YwnXp0CZroifGJARswHhYy7Ng0e-8snoW08q0bTfQmDb7QOzq6B7RrejD7g53p5GIyXdOAFnU0D7imauyo88qmrTqPEmVkIaJ3ydXSybs9ntsRqUeNU3Seqn1yCfENedUrG_Dt5b0hv799_bXdsfuf339s7-6Zzoo8sq7gXPc8Qw28r1EKkUssZVuUtcqErlrRV0XX5xWKFiXyLO-gazn0suVSKJndkI9PuumaP6d0TjOYoNFaNaI7hUZWghcV1AkIT0DtXQge-2byZlB-boA3S4rNsUkpNkuKzVIAifP-In5qB-yeGZfYEuDDBaCCVrb3atQmPONqnouiLLP_Zg2lXQ</recordid><startdate>20071015</startdate><enddate>20071015</enddate><creator>PUWEN ZHANG</creator><creator>TEREFENKO, Eugene</creator><creator>LACAVA, Margaret</creator><creator>WINNEKER, Richard C</creator><creator>ZHIMING ZHANG</creator><creator>KERN, Jeffrey</creator><creator>FENSOME, Andrew</creator><creator>TRYBULSKI, Eugene</creator><creator>UNWALLA, Ray</creator><creator>WROBEL, Jay</creator><creator>LOCKHEAD, Susan</creator><creator>YUAN ZHU</creator><creator>COHEN, Jeffrey</creator><general>Elsevier 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>7X8</scope></search><sort><creationdate>20071015</creationdate><title>5 -(3 -Cyclopentyl -2 -thioxo -2,3 -dihydro -1H -benzimidazol -5 -yl )-1-methyl -1H-pyrrole -2 -carbonitrile : A novel, highly potent, selective, and orally active non-steroidal progesterone receptor agonist</title><author>PUWEN ZHANG ; TEREFENKO, Eugene ; LACAVA, Margaret ; WINNEKER, Richard C ; ZHIMING ZHANG ; KERN, Jeffrey ; FENSOME, Andrew ; TRYBULSKI, Eugene ; UNWALLA, Ray ; WROBEL, Jay ; LOCKHEAD, Susan ; YUAN ZHU ; COHEN, Jeffrey</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c354t-d500cf03ec10f9e62246e76b579a32c8b2f85df48e2be6e034d1db01f6b062a63</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2007</creationdate><topic>Administration, Oral</topic><topic>Alkaline Phosphatase - metabolism</topic><topic>Animals</topic><topic>Biological and medical sciences</topic><topic>Cell Line, Tumor</topic><topic>Female</topic><topic>Hormones. Endocrine system</topic><topic>Medical sciences</topic><topic>Models, Molecular</topic><topic>Molecular Structure</topic><topic>Nitriles - chemistry</topic><topic>Nitriles - pharmacology</topic><topic>Pharmacology. Drug treatments</topic><topic>Pyrroles - chemistry</topic><topic>Pyrroles - pharmacology</topic><topic>Rats</topic><topic>Rats, Sprague-Dawley</topic><topic>Receptors, Progesterone - agonists</topic><topic>Receptors, Progesterone - metabolism</topic><topic>Steroids - chemistry</topic><topic>Steroids - pharmacology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>PUWEN ZHANG</creatorcontrib><creatorcontrib>TEREFENKO, Eugene</creatorcontrib><creatorcontrib>LACAVA, Margaret</creatorcontrib><creatorcontrib>WINNEKER, Richard C</creatorcontrib><creatorcontrib>ZHIMING ZHANG</creatorcontrib><creatorcontrib>KERN, Jeffrey</creatorcontrib><creatorcontrib>FENSOME, Andrew</creatorcontrib><creatorcontrib>TRYBULSKI, Eugene</creatorcontrib><creatorcontrib>UNWALLA, Ray</creatorcontrib><creatorcontrib>WROBEL, Jay</creatorcontrib><creatorcontrib>LOCKHEAD, Susan</creatorcontrib><creatorcontrib>YUAN ZHU</creatorcontrib><creatorcontrib>COHEN, Jeffrey</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>MEDLINE - Academic</collection><jtitle>Bioorganic & medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>PUWEN ZHANG</au><au>TEREFENKO, Eugene</au><au>LACAVA, Margaret</au><au>WINNEKER, Richard C</au><au>ZHIMING ZHANG</au><au>KERN, Jeffrey</au><au>FENSOME, Andrew</au><au>TRYBULSKI, Eugene</au><au>UNWALLA, Ray</au><au>WROBEL, Jay</au><au>LOCKHEAD, Susan</au><au>YUAN ZHU</au><au>COHEN, Jeffrey</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>5 -(3 -Cyclopentyl -2 -thioxo -2,3 -dihydro -1H -benzimidazol -5 -yl )-1-methyl -1H-pyrrole -2 -carbonitrile : A novel, highly potent, selective, and orally active non-steroidal progesterone receptor agonist</atitle><jtitle>Bioorganic & medicinal chemistry</jtitle><addtitle>Bioorg Med Chem</addtitle><date>2007-10-15</date><risdate>2007</risdate><volume>15</volume><issue>20</issue><spage>6556</spage><epage>6564</epage><pages>6556-6564</pages><issn>0968-0896</issn><eissn>1464-3391</eissn><abstract>We have recently discovered 5-(3-cyclopentyl-2-thioxo-2,3-dihydro-1H-benzimidazol-5-yl)-1-methyl-1H-pyrrole-2-carbonitrile (14) as a potent, selective, and orally active non-steroidal progesterone receptor (PR) agonist. Compound 14 and its analog 13 possessed sub-nanomolar in vitro potency (EC(50) 0.1-0.5nM) in the T47D alkaline phosphatase assay, similar to that of the steroidal PR agonist medroxyprogesterone acetate (MPA). In contrast to MPA, 14 was highly selective (>500-fold) for the PR over both glucocorticoid and androgen receptors. In the rat uterine decidualization and complement component C3 models, 14 had oral ED(50) values of 0.02 and 0.003mg/kg, respectively, and was from 6- to 20-fold more potent than MPA. In the monkey ovulation inhibition model, compound 14 was also highly efficacious and potent with an oral ED(100) of 0.03mg/kg.</abstract><cop>Oxford</cop><pub>Elsevier Science</pub><pmid>17681796</pmid><doi>10.1016/j.bmc.2007.07.011</doi><tpages>9</tpages></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0968-0896 |
| ispartof | Bioorganic & medicinal chemistry, 2007-10, Vol.15 (20), p.6556-6564 |
| issn | 0968-0896 1464-3391 |
| language | eng |
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| source | MEDLINE; Elsevier ScienceDirect Journals Complete |
| subjects | Administration, Oral Alkaline Phosphatase - metabolism Animals Biological and medical sciences Cell Line, Tumor Female Hormones. Endocrine system Medical sciences Models, Molecular Molecular Structure Nitriles - chemistry Nitriles - pharmacology Pharmacology. Drug treatments Pyrroles - chemistry Pyrroles - pharmacology Rats Rats, Sprague-Dawley Receptors, Progesterone - agonists Receptors, Progesterone - metabolism Steroids - chemistry Steroids - pharmacology |
| title | 5 -(3 -Cyclopentyl -2 -thioxo -2,3 -dihydro -1H -benzimidazol -5 -yl )-1-methyl -1H-pyrrole -2 -carbonitrile : A novel, highly potent, selective, and orally active non-steroidal progesterone receptor agonist |
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