Discovery of (3S,3aR)-2-(3-Chloro-4-cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylic Acid (PF-3882845), an Orally Efficacious Mineralocorticoid Receptor (MR) Antagonist for Hypertension and Nephropathy
We have discovered a novel class of nonsteroidal pyrazoline antagonists of the mineralocorticoid receptor (MR) that show excellent potency and selectivity against other nuclear receptors. Early analogues were poorly soluble and had a propensity to inhibit the hERG channel. Remarkably, both of these...
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| Veröffentlicht in: | Journal of medicinal chemistry 2010-08, Vol.53 (16), p.5979-6002 |
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| creator | Meyers, Marvin J Arhancet, Graciela B Hockerman, Susan L Chen, Xiangyang Long, Scott A Mahoney, Matthew W Rico, Joseph R Garland, Danny J Blinn, James. R Collins, Joe T Yang, Shengtian Huang, Horng-Chih McGee, Kevin F Wendling, Jay M Dietz, Jessica D Payne, Maria A Homer, Bruce L Heron, Marcia I Reitz, David B Hu, Xiao |
| description | We have discovered a novel class of nonsteroidal pyrazoline antagonists of the mineralocorticoid receptor (MR) that show excellent potency and selectivity against other nuclear receptors. Early analogues were poorly soluble and had a propensity to inhibit the hERG channel. Remarkably, both of these challenges were overcome by incorporation of a single carboxylate moiety. Structural modification of carboxylate-containing lead R -4g with a wide range of substituents at each position of the pyrazoline ring resulted in R -12o, which shows excellent activity against MR and reasonable pharmacokinetic profile. Introduction of conformational restriction led to a novel series characterized by exquisite potency and favorable steroid receptor selectivity and pharmacokinetic profile. Oral dosing of 3 S ,3a R -27d (PF-3882845) in the Dahl salt sensitive preclinical model of salt-induced hypertension and nephropathy showed blood pressure attenuation significantly greater than that with eplerenone, reduction in urinary albumin, and renal protection. As a result of these findings, 3 S ,3a R -27d was advanced to clinical studies. |
| doi_str_mv | 10.1021/jm100505n |
| format | Article |
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R ; Collins, Joe T ; Yang, Shengtian ; Huang, Horng-Chih ; McGee, Kevin F ; Wendling, Jay M ; Dietz, Jessica D ; Payne, Maria A ; Homer, Bruce L ; Heron, Marcia I ; Reitz, David B ; Hu, Xiao</creator><creatorcontrib>Meyers, Marvin J ; Arhancet, Graciela B ; Hockerman, Susan L ; Chen, Xiangyang ; Long, Scott A ; Mahoney, Matthew W ; Rico, Joseph R ; Garland, Danny J ; Blinn, James. R ; Collins, Joe T ; Yang, Shengtian ; Huang, Horng-Chih ; McGee, Kevin F ; Wendling, Jay M ; Dietz, Jessica D ; Payne, Maria A ; Homer, Bruce L ; Heron, Marcia I ; Reitz, David B ; Hu, Xiao</creatorcontrib><description>We have discovered a novel class of nonsteroidal pyrazoline antagonists of the mineralocorticoid receptor (MR) that show excellent potency and selectivity against other nuclear receptors. Early analogues were poorly soluble and had a propensity to inhibit the hERG channel. Remarkably, both of these challenges were overcome by incorporation of a single carboxylate moiety. Structural modification of carboxylate-containing lead R -4g with a wide range of substituents at each position of the pyrazoline ring resulted in R -12o, which shows excellent activity against MR and reasonable pharmacokinetic profile. Introduction of conformational restriction led to a novel series characterized by exquisite potency and favorable steroid receptor selectivity and pharmacokinetic profile. Oral dosing of 3 S ,3a R -27d (PF-3882845) in the Dahl salt sensitive preclinical model of salt-induced hypertension and nephropathy showed blood pressure attenuation significantly greater than that with eplerenone, reduction in urinary albumin, and renal protection. As a result of these findings, 3 S ,3a R -27d was advanced to clinical studies.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/jm100505n</identifier><identifier>PMID: 20672822</identifier><language>eng</language><publisher>United States: American Chemical Society</publisher><subject>Animals ; Antihypertensive Agents - chemical synthesis ; Antihypertensive Agents - pharmacokinetics ; Antihypertensive Agents - pharmacology ; Blood Pressure - drug effects ; Cell Line, Tumor ; Crystallography, X-Ray ; Humans ; Hypertension - drug therapy ; Indazoles - chemical synthesis ; Indazoles - pharmacokinetics ; Indazoles - pharmacology ; Kidney Diseases - drug therapy ; Male ; Mineralocorticoid Receptor Antagonists ; Models, Molecular ; Molecular Conformation ; Nitriles - chemical synthesis ; Nitriles - pharmacokinetics ; Nitriles - pharmacology ; Radioligand Assay ; Rats ; Rats, Inbred Dahl ; Rats, Sprague-Dawley ; Stereoisomerism ; Structure-Activity Relationship</subject><ispartof>Journal of medicinal chemistry, 2010-08, Vol.53 (16), p.5979-6002</ispartof><rights>Copyright © 2010 American Chemical Society</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://pubs.acs.org/doi/pdf/10.1021/jm100505n$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/jm100505n$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>314,777,781,27057,27905,27906,56719,56769</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/20672822$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Meyers, Marvin J</creatorcontrib><creatorcontrib>Arhancet, Graciela B</creatorcontrib><creatorcontrib>Hockerman, Susan L</creatorcontrib><creatorcontrib>Chen, Xiangyang</creatorcontrib><creatorcontrib>Long, Scott A</creatorcontrib><creatorcontrib>Mahoney, Matthew W</creatorcontrib><creatorcontrib>Rico, Joseph R</creatorcontrib><creatorcontrib>Garland, Danny J</creatorcontrib><creatorcontrib>Blinn, James. R</creatorcontrib><creatorcontrib>Collins, Joe T</creatorcontrib><creatorcontrib>Yang, Shengtian</creatorcontrib><creatorcontrib>Huang, Horng-Chih</creatorcontrib><creatorcontrib>McGee, Kevin F</creatorcontrib><creatorcontrib>Wendling, Jay M</creatorcontrib><creatorcontrib>Dietz, Jessica D</creatorcontrib><creatorcontrib>Payne, Maria A</creatorcontrib><creatorcontrib>Homer, Bruce L</creatorcontrib><creatorcontrib>Heron, Marcia I</creatorcontrib><creatorcontrib>Reitz, David B</creatorcontrib><creatorcontrib>Hu, Xiao</creatorcontrib><title>Discovery of (3S,3aR)-2-(3-Chloro-4-cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylic Acid (PF-3882845), an Orally Efficacious Mineralocorticoid Receptor (MR) Antagonist for Hypertension and Nephropathy</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>We have discovered a novel class of nonsteroidal pyrazoline antagonists of the mineralocorticoid receptor (MR) that show excellent potency and selectivity against other nuclear receptors. Early analogues were poorly soluble and had a propensity to inhibit the hERG channel. Remarkably, both of these challenges were overcome by incorporation of a single carboxylate moiety. Structural modification of carboxylate-containing lead R -4g with a wide range of substituents at each position of the pyrazoline ring resulted in R -12o, which shows excellent activity against MR and reasonable pharmacokinetic profile. Introduction of conformational restriction led to a novel series characterized by exquisite potency and favorable steroid receptor selectivity and pharmacokinetic profile. Oral dosing of 3 S ,3a R -27d (PF-3882845) in the Dahl salt sensitive preclinical model of salt-induced hypertension and nephropathy showed blood pressure attenuation significantly greater than that with eplerenone, reduction in urinary albumin, and renal protection. As a result of these findings, 3 S ,3a R -27d was advanced to clinical studies.</description><subject>Animals</subject><subject>Antihypertensive Agents - chemical synthesis</subject><subject>Antihypertensive Agents - pharmacokinetics</subject><subject>Antihypertensive Agents - pharmacology</subject><subject>Blood Pressure - drug effects</subject><subject>Cell Line, Tumor</subject><subject>Crystallography, X-Ray</subject><subject>Humans</subject><subject>Hypertension - drug therapy</subject><subject>Indazoles - chemical synthesis</subject><subject>Indazoles - pharmacokinetics</subject><subject>Indazoles - pharmacology</subject><subject>Kidney Diseases - drug therapy</subject><subject>Male</subject><subject>Mineralocorticoid Receptor Antagonists</subject><subject>Models, Molecular</subject><subject>Molecular Conformation</subject><subject>Nitriles - chemical synthesis</subject><subject>Nitriles - pharmacokinetics</subject><subject>Nitriles - pharmacology</subject><subject>Radioligand Assay</subject><subject>Rats</subject><subject>Rats, Inbred Dahl</subject><subject>Rats, Sprague-Dawley</subject><subject>Stereoisomerism</subject><subject>Structure-Activity Relationship</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2010</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNo9kUFvEzEQhS0EoqFw4A8gX5ASKYaxvbvZPUahbZBaigKcEFrNeu3G0cZeeR2E-4v7MzAqcBrN0_eeRvMIec3hHQfB3x-OHKCE0j0hM14KYEUNxVMyAxCCiUrIM_Jimg4AILmQz8mZgGolaiFm5OGDnZT_qUOi3tC5_LKUuFswweaSbfaDD54VTCV0ftxrl4YFk3lVgx-1i2lgMvPLYlmyqGPAfeqzQWxZp929_373w7oe7_2g2YopDJ3_lQar6FrZns4_XzJZ16IuysWSoqO3AYch0QtjrEJl_WmiN9bprHrlQ7TKZ9dOKz1GH-j8Zregaxfxzjs7RWqytk2jDlG7yXqXE3v6SY_74EeM-_SSPDM4TPrV33lOvl1efN1s2fXt1cfN-pqhkFVkfdNIFB1vJNcaamhKBWXRYNdXTcENoOEFGrWq6iwYA4YLLOWKV53oGtNoeU7ePOaOp-6o-3YM9oghtf9enoG3jwCqqT34U3D5nJZD-6fK9n-V8je3m44_</recordid><startdate>20100826</startdate><enddate>20100826</enddate><creator>Meyers, Marvin J</creator><creator>Arhancet, Graciela B</creator><creator>Hockerman, Susan L</creator><creator>Chen, Xiangyang</creator><creator>Long, Scott A</creator><creator>Mahoney, Matthew W</creator><creator>Rico, Joseph R</creator><creator>Garland, Danny J</creator><creator>Blinn, James. 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R</au><au>Collins, Joe T</au><au>Yang, Shengtian</au><au>Huang, Horng-Chih</au><au>McGee, Kevin F</au><au>Wendling, Jay M</au><au>Dietz, Jessica D</au><au>Payne, Maria A</au><au>Homer, Bruce L</au><au>Heron, Marcia I</au><au>Reitz, David B</au><au>Hu, Xiao</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Discovery of (3S,3aR)-2-(3-Chloro-4-cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylic Acid (PF-3882845), an Orally Efficacious Mineralocorticoid Receptor (MR) Antagonist for Hypertension and Nephropathy</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>2010-08-26</date><risdate>2010</risdate><volume>53</volume><issue>16</issue><spage>5979</spage><epage>6002</epage><pages>5979-6002</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><abstract>We have discovered a novel class of nonsteroidal pyrazoline antagonists of the mineralocorticoid receptor (MR) that show excellent potency and selectivity against other nuclear receptors. Early analogues were poorly soluble and had a propensity to inhibit the hERG channel. Remarkably, both of these challenges were overcome by incorporation of a single carboxylate moiety. Structural modification of carboxylate-containing lead R -4g with a wide range of substituents at each position of the pyrazoline ring resulted in R -12o, which shows excellent activity against MR and reasonable pharmacokinetic profile. Introduction of conformational restriction led to a novel series characterized by exquisite potency and favorable steroid receptor selectivity and pharmacokinetic profile. Oral dosing of 3 S ,3a R -27d (PF-3882845) in the Dahl salt sensitive preclinical model of salt-induced hypertension and nephropathy showed blood pressure attenuation significantly greater than that with eplerenone, reduction in urinary albumin, and renal protection. As a result of these findings, 3 S ,3a R -27d was advanced to clinical studies.</abstract><cop>United States</cop><pub>American Chemical Society</pub><pmid>20672822</pmid><doi>10.1021/jm100505n</doi><tpages>24</tpages></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0022-2623 |
| ispartof | Journal of medicinal chemistry, 2010-08, Vol.53 (16), p.5979-6002 |
| issn | 0022-2623 1520-4804 |
| language | eng |
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| source | MEDLINE; ACS Publications |
| subjects | Animals Antihypertensive Agents - chemical synthesis Antihypertensive Agents - pharmacokinetics Antihypertensive Agents - pharmacology Blood Pressure - drug effects Cell Line, Tumor Crystallography, X-Ray Humans Hypertension - drug therapy Indazoles - chemical synthesis Indazoles - pharmacokinetics Indazoles - pharmacology Kidney Diseases - drug therapy Male Mineralocorticoid Receptor Antagonists Models, Molecular Molecular Conformation Nitriles - chemical synthesis Nitriles - pharmacokinetics Nitriles - pharmacology Radioligand Assay Rats Rats, Inbred Dahl Rats, Sprague-Dawley Stereoisomerism Structure-Activity Relationship |
| title | Discovery of (3S,3aR)-2-(3-Chloro-4-cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylic Acid (PF-3882845), an Orally Efficacious Mineralocorticoid Receptor (MR) Antagonist for Hypertension and Nephropathy |
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