In vitro and in vivo characterization of novel nonsteroidal progesterone receptor antagonists derived from the fungal metabolite PF1092C
We studied the pharmacological effects of novel nonsteroidal progesterone receptor antagonists CP8661 and CP8754, which were synthesized from the fungal metabolite PF1092C. CP8661 possess a tetrahydrobenzindolone skeleton and CP8754 possess a tetrahydronaphthofuranone skeleton. In binding assays for...
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| Veröffentlicht in: | The Journal of steroid biochemistry and molecular biology 2002-10, Vol.82 (2), p.217-223 |
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| container_title | The Journal of steroid biochemistry and molecular biology |
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| creator | Tabata, Yuji Iizuka, Yumiko Masuda, Naomi Takei Shinei, Rie Kurihara, Ken-ichi Okonogi, Tsuneo Hoshiko, Shigeru Kurata, Yasushi |
| description | We studied the pharmacological effects of novel nonsteroidal progesterone receptor antagonists CP8661 and CP8754, which were synthesized from the fungal metabolite PF1092C. CP8661 possess a tetrahydrobenzindolone skeleton and CP8754 possess a tetrahydronaphthofuranone skeleton. In binding assays for steroid receptors, CP8661 and CP8754 inhibited [
3H]-progesterone binding to human progesterone receptors (hPR), though they are less potent than RU486. CP8661 also showed moderate affinity to rat androgen receptors (rAR), although CP8754 did not. Neither compound showed affinity to human glucocorticoid receptors (hGR) or human estrogen receptors (hER). In exogeneous and endogeneous PR-dependent enzyme expression assays using human mammary carcinoma T47D, CP8661 and CP8754 showed pure antagonistic activity. In a rabbit endometrial transformation test, CP8661 and CP8754 showed anti-progestational activity by s.c. administration in a dose-dependent manner; meanwhile, these compounds showed no progestational activity at the same dose. These results suggested that CP8661 and CP8754 are in vivo effective pure progesterone receptor antagonists and presented the possibility of synthesizing pure progesterone receptor antagonists from both tetrahydronaphthofuranone and tetrahydrobenzindolone skeletons. |
| doi_str_mv | 10.1016/S0960-0760(02)00157-7 |
| format | Article |
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3H]-progesterone binding to human progesterone receptors (hPR), though they are less potent than RU486. CP8661 also showed moderate affinity to rat androgen receptors (rAR), although CP8754 did not. Neither compound showed affinity to human glucocorticoid receptors (hGR) or human estrogen receptors (hER). In exogeneous and endogeneous PR-dependent enzyme expression assays using human mammary carcinoma T47D, CP8661 and CP8754 showed pure antagonistic activity. In a rabbit endometrial transformation test, CP8661 and CP8754 showed anti-progestational activity by s.c. administration in a dose-dependent manner; meanwhile, these compounds showed no progestational activity at the same dose. These results suggested that CP8661 and CP8754 are in vivo effective pure progesterone receptor antagonists and presented the possibility of synthesizing pure progesterone receptor antagonists from both tetrahydronaphthofuranone and tetrahydrobenzindolone skeletons.</description><identifier>ISSN: 0960-0760</identifier><identifier>EISSN: 1879-1220</identifier><identifier>DOI: 10.1016/S0960-0760(02)00157-7</identifier><identifier>PMID: 12477488</identifier><language>eng</language><publisher>Oxford: Elsevier Ltd</publisher><subject>Animals ; Biological and medical sciences ; Biological Assay ; Dose-Response Relationship, Drug ; Endometrium - metabolism ; Estrogens - metabolism ; Female ; Gene Expression Regulation ; Genes, Reporter ; Genital system. Reproduction ; Hormone Antagonists - chemistry ; Hormone Antagonists - metabolism ; Hormone Antagonists - pharmacology ; Humans ; McPhail test ; Medical sciences ; Molecular Structure ; Naphthols - chemistry ; Naphthols - metabolism ; Naphthols - pharmacology ; Nonsteroidal progesterone receptor antagonist ; PF1092 ; Pharmacology. Drug treatments ; Progesterone - chemistry ; Progesterone - metabolism ; Rabbits ; Receptors, Androgen - metabolism ; Receptors, Estrogen - metabolism ; Receptors, Progesterone - antagonists & inhibitors ; Receptors, Progesterone - metabolism ; Sesquiterpenes - chemistry ; Sesquiterpenes - metabolism ; Sesquiterpenes - pharmacology ; T47D ; Tetrahydrobenzindolone ; Tetrahydronaphthofuranone ; Tumor Cells, Cultured</subject><ispartof>The Journal of steroid biochemistry and molecular biology, 2002-10, Vol.82 (2), p.217-223</ispartof><rights>2002 Elsevier Science Ltd</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c391t-17f0f9c842f9c3b5d2a0ca6d22084c8648e8de9420d4976581cd85da709f95663</citedby><cites>FETCH-LOGICAL-c391t-17f0f9c842f9c3b5d2a0ca6d22084c8648e8de9420d4976581cd85da709f95663</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0960076002001577$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,776,780,3537,27901,27902,65306</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=14881083$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/12477488$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Tabata, Yuji</creatorcontrib><creatorcontrib>Iizuka, Yumiko</creatorcontrib><creatorcontrib>Masuda, Naomi Takei</creatorcontrib><creatorcontrib>Shinei, Rie</creatorcontrib><creatorcontrib>Kurihara, Ken-ichi</creatorcontrib><creatorcontrib>Okonogi, Tsuneo</creatorcontrib><creatorcontrib>Hoshiko, Shigeru</creatorcontrib><creatorcontrib>Kurata, Yasushi</creatorcontrib><title>In vitro and in vivo characterization of novel nonsteroidal progesterone receptor antagonists derived from the fungal metabolite PF1092C</title><title>The Journal of steroid biochemistry and molecular biology</title><addtitle>J Steroid Biochem Mol Biol</addtitle><description>We studied the pharmacological effects of novel nonsteroidal progesterone receptor antagonists CP8661 and CP8754, which were synthesized from the fungal metabolite PF1092C. CP8661 possess a tetrahydrobenzindolone skeleton and CP8754 possess a tetrahydronaphthofuranone skeleton. In binding assays for steroid receptors, CP8661 and CP8754 inhibited [
3H]-progesterone binding to human progesterone receptors (hPR), though they are less potent than RU486. CP8661 also showed moderate affinity to rat androgen receptors (rAR), although CP8754 did not. Neither compound showed affinity to human glucocorticoid receptors (hGR) or human estrogen receptors (hER). In exogeneous and endogeneous PR-dependent enzyme expression assays using human mammary carcinoma T47D, CP8661 and CP8754 showed pure antagonistic activity. In a rabbit endometrial transformation test, CP8661 and CP8754 showed anti-progestational activity by s.c. administration in a dose-dependent manner; meanwhile, these compounds showed no progestational activity at the same dose. These results suggested that CP8661 and CP8754 are in vivo effective pure progesterone receptor antagonists and presented the possibility of synthesizing pure progesterone receptor antagonists from both tetrahydronaphthofuranone and tetrahydrobenzindolone skeletons.</description><subject>Animals</subject><subject>Biological and medical sciences</subject><subject>Biological Assay</subject><subject>Dose-Response Relationship, Drug</subject><subject>Endometrium - metabolism</subject><subject>Estrogens - metabolism</subject><subject>Female</subject><subject>Gene Expression Regulation</subject><subject>Genes, Reporter</subject><subject>Genital system. Reproduction</subject><subject>Hormone Antagonists - chemistry</subject><subject>Hormone Antagonists - metabolism</subject><subject>Hormone Antagonists - pharmacology</subject><subject>Humans</subject><subject>McPhail test</subject><subject>Medical sciences</subject><subject>Molecular Structure</subject><subject>Naphthols - chemistry</subject><subject>Naphthols - metabolism</subject><subject>Naphthols - pharmacology</subject><subject>Nonsteroidal progesterone receptor antagonist</subject><subject>PF1092</subject><subject>Pharmacology. Drug treatments</subject><subject>Progesterone - chemistry</subject><subject>Progesterone - metabolism</subject><subject>Rabbits</subject><subject>Receptors, Androgen - metabolism</subject><subject>Receptors, Estrogen - metabolism</subject><subject>Receptors, Progesterone - antagonists & inhibitors</subject><subject>Receptors, Progesterone - metabolism</subject><subject>Sesquiterpenes - chemistry</subject><subject>Sesquiterpenes - metabolism</subject><subject>Sesquiterpenes - pharmacology</subject><subject>T47D</subject><subject>Tetrahydrobenzindolone</subject><subject>Tetrahydronaphthofuranone</subject><subject>Tumor Cells, Cultured</subject><issn>0960-0760</issn><issn>1879-1220</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2002</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkc2OVCEQhYnROO3oI2jYaHRxteD-wF1NTMfRSSbRRF0TGooezL3QAn0TfQIfW_onztJNkSLfORSnCHnO4C0DNrz7CuMADYgBXgN_A8B60YgHZMWkGBvGOTwkq3_IBXmS8w8AaFsmHpMLxjshOilX5M9NoIsvKVIdLPWHZonU3OmkTcHkf-viY6DR0RAXnGoNud5Hb_VEdylu8dgGpAkN7kpM1ajobQw-l0xttVjQUpfiTMsdUrcP26qcsehNnHxB-uWawcjXT8kjp6eMz87nJfl-_eHb-lNz-_njzfr9bWPakZWGCQduNLLjtbab3nINRg-2flh2Rg6dRGlx7DjYbhRDL5mxsrdawOjGfhjaS_Lq5FuH_7mv06vZZ4PTpAPGfVaCi77joqtgfwJNijkndGqX_KzTL8VAHVagjitQh3wVcHVcgRJV9-L8wH4zo71XnTOvwMszoLPRk0s6GJ_vucowkG3lrk4c1jgWj0ll4zEYtL5mXZSN_j-j_AUhXaSy</recordid><startdate>20021001</startdate><enddate>20021001</enddate><creator>Tabata, Yuji</creator><creator>Iizuka, Yumiko</creator><creator>Masuda, Naomi Takei</creator><creator>Shinei, Rie</creator><creator>Kurihara, Ken-ichi</creator><creator>Okonogi, Tsuneo</creator><creator>Hoshiko, Shigeru</creator><creator>Kurata, Yasushi</creator><general>Elsevier Ltd</general><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>20021001</creationdate><title>In vitro and in vivo characterization of novel nonsteroidal progesterone receptor antagonists derived from the fungal metabolite PF1092C</title><author>Tabata, Yuji ; Iizuka, Yumiko ; Masuda, Naomi Takei ; Shinei, Rie ; Kurihara, Ken-ichi ; Okonogi, Tsuneo ; Hoshiko, Shigeru ; Kurata, Yasushi</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c391t-17f0f9c842f9c3b5d2a0ca6d22084c8648e8de9420d4976581cd85da709f95663</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2002</creationdate><topic>Animals</topic><topic>Biological and medical sciences</topic><topic>Biological Assay</topic><topic>Dose-Response Relationship, Drug</topic><topic>Endometrium - metabolism</topic><topic>Estrogens - metabolism</topic><topic>Female</topic><topic>Gene Expression Regulation</topic><topic>Genes, Reporter</topic><topic>Genital system. Reproduction</topic><topic>Hormone Antagonists - chemistry</topic><topic>Hormone Antagonists - metabolism</topic><topic>Hormone Antagonists - pharmacology</topic><topic>Humans</topic><topic>McPhail test</topic><topic>Medical sciences</topic><topic>Molecular Structure</topic><topic>Naphthols - chemistry</topic><topic>Naphthols - metabolism</topic><topic>Naphthols - pharmacology</topic><topic>Nonsteroidal progesterone receptor antagonist</topic><topic>PF1092</topic><topic>Pharmacology. Drug treatments</topic><topic>Progesterone - chemistry</topic><topic>Progesterone - metabolism</topic><topic>Rabbits</topic><topic>Receptors, Androgen - metabolism</topic><topic>Receptors, Estrogen - metabolism</topic><topic>Receptors, Progesterone - antagonists & inhibitors</topic><topic>Receptors, Progesterone - metabolism</topic><topic>Sesquiterpenes - chemistry</topic><topic>Sesquiterpenes - metabolism</topic><topic>Sesquiterpenes - pharmacology</topic><topic>T47D</topic><topic>Tetrahydrobenzindolone</topic><topic>Tetrahydronaphthofuranone</topic><topic>Tumor Cells, Cultured</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Tabata, Yuji</creatorcontrib><creatorcontrib>Iizuka, Yumiko</creatorcontrib><creatorcontrib>Masuda, Naomi Takei</creatorcontrib><creatorcontrib>Shinei, Rie</creatorcontrib><creatorcontrib>Kurihara, Ken-ichi</creatorcontrib><creatorcontrib>Okonogi, Tsuneo</creatorcontrib><creatorcontrib>Hoshiko, Shigeru</creatorcontrib><creatorcontrib>Kurata, Yasushi</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>The Journal of steroid biochemistry and molecular biology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Tabata, Yuji</au><au>Iizuka, Yumiko</au><au>Masuda, Naomi Takei</au><au>Shinei, Rie</au><au>Kurihara, Ken-ichi</au><au>Okonogi, Tsuneo</au><au>Hoshiko, Shigeru</au><au>Kurata, Yasushi</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>In vitro and in vivo characterization of novel nonsteroidal progesterone receptor antagonists derived from the fungal metabolite PF1092C</atitle><jtitle>The Journal of steroid biochemistry and molecular biology</jtitle><addtitle>J Steroid Biochem Mol Biol</addtitle><date>2002-10-01</date><risdate>2002</risdate><volume>82</volume><issue>2</issue><spage>217</spage><epage>223</epage><pages>217-223</pages><issn>0960-0760</issn><eissn>1879-1220</eissn><abstract>We studied the pharmacological effects of novel nonsteroidal progesterone receptor antagonists CP8661 and CP8754, which were synthesized from the fungal metabolite PF1092C. CP8661 possess a tetrahydrobenzindolone skeleton and CP8754 possess a tetrahydronaphthofuranone skeleton. In binding assays for steroid receptors, CP8661 and CP8754 inhibited [
3H]-progesterone binding to human progesterone receptors (hPR), though they are less potent than RU486. CP8661 also showed moderate affinity to rat androgen receptors (rAR), although CP8754 did not. Neither compound showed affinity to human glucocorticoid receptors (hGR) or human estrogen receptors (hER). In exogeneous and endogeneous PR-dependent enzyme expression assays using human mammary carcinoma T47D, CP8661 and CP8754 showed pure antagonistic activity. In a rabbit endometrial transformation test, CP8661 and CP8754 showed anti-progestational activity by s.c. administration in a dose-dependent manner; meanwhile, these compounds showed no progestational activity at the same dose. These results suggested that CP8661 and CP8754 are in vivo effective pure progesterone receptor antagonists and presented the possibility of synthesizing pure progesterone receptor antagonists from both tetrahydronaphthofuranone and tetrahydrobenzindolone skeletons.</abstract><cop>Oxford</cop><pub>Elsevier Ltd</pub><pmid>12477488</pmid><doi>10.1016/S0960-0760(02)00157-7</doi><tpages>7</tpages></addata></record> |
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| subjects | Animals Biological and medical sciences Biological Assay Dose-Response Relationship, Drug Endometrium - metabolism Estrogens - metabolism Female Gene Expression Regulation Genes, Reporter Genital system. Reproduction Hormone Antagonists - chemistry Hormone Antagonists - metabolism Hormone Antagonists - pharmacology Humans McPhail test Medical sciences Molecular Structure Naphthols - chemistry Naphthols - metabolism Naphthols - pharmacology Nonsteroidal progesterone receptor antagonist PF1092 Pharmacology. Drug treatments Progesterone - chemistry Progesterone - metabolism Rabbits Receptors, Androgen - metabolism Receptors, Estrogen - metabolism Receptors, Progesterone - antagonists & inhibitors Receptors, Progesterone - metabolism Sesquiterpenes - chemistry Sesquiterpenes - metabolism Sesquiterpenes - pharmacology T47D Tetrahydrobenzindolone Tetrahydronaphthofuranone Tumor Cells, Cultured |
| title | In vitro and in vivo characterization of novel nonsteroidal progesterone receptor antagonists derived from the fungal metabolite PF1092C |
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