{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T16:12:28Z","timestamp":1791216748331,"version":"4.1.0"},"reference-count":30,"publisher":"The Endocrine Society","issue":"8","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2011,8,1]]},"abstract":"<jats:p>A synthetic glucocorticoid receptor (GR) ligand with the efficacy of a glucocorticoid, but without the accompanying side effects, would meet an unmet medical need for the treatment of inflammatory diseases. It was hypothesized that a GR ligand that shifted helix 12 in a manner distinct from an agonist and an antagonist would confer a distinct GR conformation, resulting in differential gene expression and, ultimately, dissociation of antiinflammatory activity from side effects. A structural feature expected to interfere with helix 12 was incorporated into a nonsteroidal, tricyclic scaffold to create novel, high-affinity, and selective GR ligands that manifested a dual function in cellular assays, partial but robust agonist activity for inflammatory cytokine inhibition, and full antagonist activity for reporter gene activation. In contrast, analogs not likely to hinder helix 12 exhibited partial agonist activity for reporter gene activation. The requirement of full antagonist activity for substantial side effect dissociation was demonstrated in primary human preadipocytes, hepatocytes, and osteoblasts in which effects on adipogenesis, key genes involved in gluconeogenesis, and genes important for bone formation were examined, respectively. The dissociated GR ligands, despite lacking significant reporter gene activation, weakly recruit a limited number of coactivators such as peroxisomal proliferator-activated receptor-\u03b3 coactivator 1\u03b1. Transcriptional activation was sensitive to both peroxisomal proliferator-activated receptor-\u03b3 coactivator 1\u03b1 and GR levels, providing a basis for cell-selective modulation of gene expression. The antiinflammatory activity of the dissociated ligands was further demonstrated in mouse models of inflammation. Together these results suggest that these ligands are promising candidates with robust antiinflammatory activity and likely dissociation against glucocorticoid-induced side effects.<\/jats:p>","DOI":"10.1210\/en.2010-1447","type":"journal-article","created":{"date-parts":[[2011,5,11]],"date-time":"2011-05-11T01:14:00Z","timestamp":1305076440000},"page":"3123-3134","source":"Crossref","is-referenced-by-count":60,"title":["The Antagonists But Not Partial Agonists of Glucocorticoid Receptor Ligands Show Substantial Side Effect Dissociation"],"prefix":"10.1210","volume":"152","author":[{"given":"Xiao","family":"Hu","sequence":"first","affiliation":[{"name":"St. Louis Laboratories, Discovery Biology and Chemistry, Pfizer Global Research and Development, St. Louis, Missouri 63017"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah","family":"Du","sequence":"first","affiliation":[{"name":"St. Louis Laboratories, Discovery Biology and Chemistry, Pfizer Global Research and Development, St. Louis, Missouri 63017"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cansu","family":"Tunca","sequence":"first","affiliation":[{"name":"St. Louis Laboratories, Discovery Biology and Chemistry, Pfizer Global Research and Development, St. Louis, Missouri 63017"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Timothy","family":"Braden","sequence":"first","affiliation":[{"name":"St. Louis Laboratories, Discovery Biology and Chemistry, Pfizer Global Research and Development, St. Louis, Missouri 63017"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kelly R.","family":"Long","sequence":"first","affiliation":[{"name":"St. Louis Laboratories, Discovery Biology and Chemistry, Pfizer Global Research and Development, St. Louis, Missouri 63017"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jamie","family":"Lee","sequence":"first","affiliation":[{"name":"St. Louis Laboratories, Discovery Biology and Chemistry, Pfizer Global Research and Development, St. Louis, Missouri 63017"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth G.","family":"Webb","sequence":"first","affiliation":[{"name":"St. Louis Laboratories, Discovery Biology and Chemistry, Pfizer Global Research and Development, St. Louis, Missouri 63017"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jessica D.","family":"Dietz","sequence":"first","affiliation":[{"name":"St. Louis Laboratories, Discovery Biology and Chemistry, Pfizer Global Research and Development, St. Louis, Missouri 63017"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susan","family":"Hummert","sequence":"first","affiliation":[{"name":"St. Louis Laboratories, Discovery Biology and Chemistry, Pfizer Global Research and Development, St. Louis, Missouri 63017"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sharon","family":"Rouw","sequence":"first","affiliation":[{"name":"St. Louis Laboratories, Discovery Biology and Chemistry, Pfizer Global Research and Development, St. Louis, Missouri 63017"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shridhar G.","family":"Hegde","sequence":"first","affiliation":[{"name":"St. Louis Laboratories, Discovery Biology and Chemistry, Pfizer Global Research and Development, St. Louis, Missouri 63017"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"R. Keith","family":"Webber","sequence":"first","affiliation":[{"name":"St. Louis Laboratories, Discovery Biology and Chemistry, Pfizer Global Research and Development, St. Louis, Missouri 63017"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark G.","family":"Obukowicz","sequence":"first","affiliation":[{"name":"St. Louis Laboratories, Discovery Biology and Chemistry, Pfizer Global Research and Development, St. Louis, Missouri 63017"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"80","published-online":{"date-parts":[[2011,5,10]]},"reference":[{"key":"2020071613045759300_B1","doi-asserted-by":"crossref","first-page":"1711","DOI":"10.1056\/NEJMra050541","article-title":"Antiinflammatory action of glucocorticoids\u2014new mechanisms for old drugs.","volume":"353","author":"Rhen","year":"2005","journal-title":"N Engl J Med"},{"key":"2020071613045759300_B2","doi-asserted-by":"crossref","first-page":"488","DOI":"10.1210\/er.2002-0006","article-title":"The interplay between the glucocorticoid receptor and nuclear factor-\u03baB or activator protein-1: molecular mechanisms for gene repression.","volume":"24","author":"De Bosscher","year":"2003","journal-title":"Endocr Rev"},{"key":"2020071613045759300_B3","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1016\/S0163-7258(02)00297-8","article-title":"Mechanisms involved in the side effects of glucocorticoids.","volume":"96","author":"Sch\u00e4cke","year":"2002","journal-title":"Pharmacol Ther"},{"key":"2020071613045759300_B4","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1111\/j.1365-2362.2008.02067.x","article-title":"Novel insights into glucocorticoid-mediated diabetogenic effects: towards expansion of therapeutic options?","volume":"39","author":"van Raalte","year":"2009","journal-title":"Eur J Clin Invest"},{"key":"2020071613045759300_B5","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1111\/j.1749-6632.2002.tb04204.x","article-title":"Mechanisms of glucocorticoid action in bone.","volume":"966","author":"Canalis","year":"2002","journal-title":"Ann NY Acad Sci"},{"key":"2020071613045759300_B6","doi-asserted-by":"crossref","first-page":"924","DOI":"10.1016\/S8756-3282(02)00737-8","article-title":"Glucocorticoid-induced osteopenia in the mouse as assessed by histomorphometry, microcomputed tomography, and biochemical markers.","volume":"30","author":"McLaughlin","year":"2002","journal-title":"Bone"},{"key":"2020071613045759300_B7","doi-asserted-by":"crossref","first-page":"1056","DOI":"10.1210\/jcem-62-5-1056","article-title":"Serum osteocalcin is increased in patients with hyperthyroidism and decreased in patients receiving glucocorticoids.","volume":"62","author":"Lukert","year":"1986","journal-title":"J Clin Endocrinol Metab"},{"key":"2020071613045759300_B8","doi-asserted-by":"crossref","first-page":"5284","DOI":"10.1210\/en.2006-0267","article-title":"Modulation of early human preadipocyte differentiation by glucocorticoids.","volume":"147","author":"Tomlinson","year":"2006","journal-title":"Endocrinology"},{"key":"2020071613045759300_B9","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1038\/ncprheum0070","article-title":"Mechanisms of disease: is osteoporosis the obesity of bone?","volume":"2","author":"Rosen","year":"2006","journal-title":"Nat Clin Pract Rheumatol"},{"key":"2020071613045759300_B10","doi-asserted-by":"crossref","first-page":"799","DOI":"10.1124\/mol.107.038794","article-title":"Separating transrepression and transactivation: a distressing divorce for the glucocorticoid receptor?","volume":"72","author":"Newton","year":"2007","journal-title":"Mol Pharmacol"},{"key":"2020071613045759300_B11","doi-asserted-by":"crossref","first-page":"452","DOI":"10.1210\/er.2005-0002","article-title":"The search for safer glucocorticoid receptor ligands.","volume":"26","author":"Rosen","year":"2005","journal-title":"Endocr Rev"},{"key":"2020071613045759300_B12","doi-asserted-by":"crossref","first-page":"750","DOI":"10.2174\/156802608784535048","article-title":"Recent developments in the discovery of selective glucocorticoid receptor modulators (SGRMs).","volume":"8","author":"Hudson","year":"2008","journal-title":"Curr Top Med Chem"},{"key":"2020071613045759300_B13","doi-asserted-by":"crossref","first-page":"521","DOI":"10.2174\/156802608783955737","article-title":"Recent progress in the discovery of novel glucocorticoid receptor modulators.","volume":"8","author":"Takahashi","year":"2008","journal-title":"Curr Top Med Chem"},{"key":"2020071613045759300_B14","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1016\/S0092-8674(02)00817-6","article-title":"Crystal structure of the glucocorticoid receptor ligand binding domain reveals a novel mode of receptor dimerization and coactivator recognition.","volume":"110","author":"Bledsoe","year":"2002","journal-title":"Cell"},{"key":"2020071613045759300_B15","doi-asserted-by":"crossref","first-page":"22748","DOI":"10.1074\/jbc.M212711200","article-title":"The three-dimensional structures of antagonistic and agonistic forms of the glucocorticoid receptor ligand-binding domain: RU-486 induces a transconformation that leads to active antagonism.","volume":"278","author":"Kauppi","year":"2003","journal-title":"J Biol Chem"},{"key":"2020071613045759300_B16","first-page":"1222","article-title":"CBP (CREB binding protein) integrates NF-\u03baB (nuclear factor-\u03baB) and glucocorticoid receptor physical interactions and antagonism.","volume":"14","author":"McKay","year":"2000","journal-title":"Mol Endocrinol"},{"key":"2020071613045759300_B17","doi-asserted-by":"crossref","first-page":"16701","DOI":"10.1073\/pnas.262671599","article-title":"Alternate surfaces of transcriptional coregulator GRIP1 function in different glucocorticoid receptor activation and repression contexts.","volume":"99","author":"Rogatsky","year":"2002","journal-title":"Proc Natl Acad Sci USA"},{"key":"2020071613045759300_B18","doi-asserted-by":"crossref","first-page":"1460","DOI":"10.1210\/me.2004-0537","article-title":"The ligand-dependent interaction of mineralocorticoid receptor with coactivator and corepressor peptides suggests multiple activation mechanisms.","volume":"19","author":"Hultman","year":"2005","journal-title":"Mol Endocrinol"},{"key":"2020071613045759300_B19","doi-asserted-by":"crossref","first-page":"2417","DOI":"10.1021\/jm0105530","article-title":"Discovery of potent, nonsteroidal, and highly selective glucocorticoid receptor antagonists.","volume":"45","author":"Morgan","year":"2002","journal-title":"J Med Chem"},{"key":"2020071613045759300_B20","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1111\/j.1365-2265.1988.tb03673.x","article-title":"Glucocorticoids and glucose metabolism: hepatic glucose production in untreated Addisonian patients and on two different levels of glucocorticoid administration.","volume":"28","author":"Malerbi","year":"1988","journal-title":"Clin Endocrinol (Oxf)"},{"key":"2020071613045759300_B21","first-page":"S64","article-title":"Corticosteroid-induced osteoporosis: pathogenesis and prevention.","volume":"18","author":"Benvenuti","year":"2000","journal-title":"Clin Exp Rheumatol"},{"key":"2020071613045759300_B22","doi-asserted-by":"crossref","first-page":"1471","DOI":"10.1210\/me.2005-0247","article-title":"The evolution of mineralocorticoid receptors.","volume":"20","author":"Hu","year":"2006","journal-title":"Mol Endocrinol"},{"key":"2020071613045759300_B23","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1038\/35093050","article-title":"Control of hepatic gluconeogenesis through the transcriptional coactivator PGC-1.","volume":"413","author":"Yoon","year":"2001","journal-title":"Nature"},{"key":"2020071613045759300_B24","doi-asserted-by":"crossref","first-page":"689","DOI":"10.1101\/gad.1400506","article-title":"Novel arylpyrazole compounds selectively modulate glucocorticoid receptor regulatory activity.","volume":"20","author":"Wang","year":"2006","journal-title":"Genes Dev"},{"key":"2020071613045759300_B25","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1073\/pnas.0300372101","article-title":"Dissociation of transactivation from transrepression by a selective glucocorticoid receptor agonist leads to separation of therapeutic effects from side effects.","volume":"101","author":"Sch\u00e4cke","year":"2004","journal-title":"Proc Natl Acad Sci USA"},{"key":"2020071613045759300_B26","doi-asserted-by":"crossref","first-page":"19244","DOI":"10.1073\/pnas.0705517104","article-title":"Antiinflammatory glucocorticoid receptor ligand with reduced side effects exhibits an altered protein-protein interaction profile.","volume":"104","author":"Miner","year":"2007","journal-title":"Proc Natl Acad Sci USA"},{"key":"2020071613045759300_B27","doi-asserted-by":"crossref","first-page":"860","DOI":"10.1210\/me.2002-0355","article-title":"A novel antiinflammatory maintains glucocorticoid efficacy with reduced side effects.","volume":"17","author":"Coghlan","year":"2003","journal-title":"Mol Endocrinol"},{"key":"2020071613045759300_B28","doi-asserted-by":"crossref","first-page":"15827","DOI":"10.1073\/pnas.0505554102","article-title":"A fully dissociated compound of plant origin for inflammatory gene repression.","volume":"102","author":"De Bosscher","year":"2005","journal-title":"Proc Natl Acad Sci USA"},{"key":"2020071613045759300_B29","doi-asserted-by":"crossref","first-page":"3241","DOI":"10.1002\/art.24963","article-title":"Differential mechanism of NF-\u03baB inhibition by two glucocorticoid receptor modulators in rheumatoid arthritis synovial fibroblasts.","volume":"60","author":"Gossye","year":"2009","journal-title":"Arthritis Rheum"},{"key":"2020071613045759300_B30","doi-asserted-by":"crossref","first-page":"4373","DOI":"10.1182\/blood-2006-07-038026","article-title":"Inhibition of adhesive interaction between multiple myeloma and bone marrow stromal cells by PPAR\u03b3 cross talk with NF-\u03baB and C\/EBP.","volume":"110","author":"Wang","year":"2007","journal-title":"Blood"}],"container-title":["Endocrinology"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/academic.oup.com\/endo\/article-pdf\/152\/8\/3123\/9039144\/endo3123.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/academic.oup.com\/endo\/article-pdf\/152\/8\/3123\/9039144\/endo3123.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2020,7,16]],"date-time":"2020-07-16T22:55:59Z","timestamp":1594940159000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/endo\/article\/152\/8\/3123\/2457271"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2011,5,10]]},"references-count":30,"journal-issue":{"issue":"8","published-print":{"date-parts":[[2011,8,1]]}},"URL":"https:\/\/doi.org\/10.1210\/en.2010-1447","relation":{},"ISSN":["0013-7227","1945-7170"],"issn-type":[{"value":"0013-7227","type":"print"},{"value":"1945-7170","type":"electronic"}],"subject":[],"published":{"date-parts":[[2011,5,10]]}}}