{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T21:22:02Z","timestamp":1791494522689,"version":"4.3.4"},"reference-count":44,"publisher":"The Endocrine Society","issue":"5","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2003,5,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Glucocorticoids (GCs) are commonly used to treat inflammatory disease; unfortunately, the long-term use of these steroids leads to a large number of debilitating side effects. The antiinflammatory effects of GCs are a result of GC receptor (GR)-mediated inhibition of expression of proinflammatory genes as well as GR-mediated activation of antiinflammatory genes. Similarly, side effects are most likely due to both activated and repressed GR target genes in affected tissues. An as yet unachieved pharmaceutical goal is the development of a compound capable of separating detrimental side effects from antiinflammatory activity. We describe the discovery and characterization of AL-438, a GR ligand that exhibits an altered gene regulation profile, able to repress and activate only a subset of the genes normally regulated by GCs. When tested in vivo, AL-438 retains full antiinflammatory efficacy and potency comparable to steroids but its negative effects on bone metabolism and glucose control are reduced at equivalently antiinflammatory doses. The mechanism underlying this selective in vitro and in vivo activity may be the result of differential cofactor recruitment in response to ligand. AL-438 reduces the interaction between GR and peroxisomal proliferator-activated receptor \u03b3 coactivator-1, a cofactor critical for steroid-mediated glucose up-regulation, while maintaining normal interactions with GR-interacting protein 1. This compound serves as a prototype for a unique, nonsteroidal alternative to conventional GCs in treating inflammatory disease.<\/jats:p>","DOI":"10.1210\/me.2002-0355","type":"journal-article","created":{"date-parts":[[2003,4,25]],"date-time":"2003-04-25T22:18:59Z","timestamp":1051309139000},"page":"860-869","source":"Crossref","is-referenced-by-count":193,"title":["A Novel Antiinflammatory Maintains Glucocorticoid Efficacy with Reduced Side Effects"],"prefix":"10.1210","volume":"17","author":[{"given":"Michael J.","family":"Coghlan","sequence":"first","affiliation":[{"name":"Abbott Laboratories (M.J.C., P.B.J., B.L., M.N., C.W.L., S.W.E., P.R.K., J.R.L., G.W.C.), Abbott Park, Illinois 60064"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peer B.","family":"Jacobson","sequence":"additional","affiliation":[{"name":"Abbott Laboratories (M.J.C., P.B.J., B.L., M.N., C.W.L., S.W.E., P.R.K., J.R.L., G.W.C.), Abbott Park, Illinois 60064"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ben","family":"Lane","sequence":"additional","affiliation":[{"name":"Abbott Laboratories (M.J.C., P.B.J., B.L., M.N., C.W.L., S.W.E., P.R.K., J.R.L., G.W.C.), Abbott Park, Illinois 60064"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masaki","family":"Nakane","sequence":"additional","affiliation":[{"name":"Abbott Laboratories (M.J.C., P.B.J., B.L., M.N., C.W.L., S.W.E., P.R.K., J.R.L., G.W.C.), Abbott Park, Illinois 60064"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chun Wei","family":"Lin","sequence":"additional","affiliation":[{"name":"Abbott Laboratories (M.J.C., P.B.J., B.L., M.N., C.W.L., S.W.E., P.R.K., J.R.L., G.W.C.), Abbott Park, Illinois 60064"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven W.","family":"Elmore","sequence":"additional","affiliation":[{"name":"Abbott Laboratories (M.J.C., P.B.J., B.L., M.N., C.W.L., S.W.E., P.R.K., J.R.L., G.W.C.), Abbott Park, Illinois 60064"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philip R.","family":"Kym","sequence":"additional","affiliation":[{"name":"Abbott Laboratories (M.J.C., P.B.J., B.L., M.N., C.W.L., S.W.E., P.R.K., J.R.L., G.W.C.), Abbott Park, Illinois 60064"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jay R.","family":"Luly","sequence":"additional","affiliation":[{"name":"Abbott Laboratories (M.J.C., P.B.J., B.L., M.N., C.W.L., S.W.E., P.R.K., J.R.L., G.W.C.), Abbott Park, Illinois 60064"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"George W.","family":"Carter","sequence":"additional","affiliation":[{"name":"Abbott Laboratories (M.J.C., P.B.J., B.L., M.N., C.W.L., S.W.E., P.R.K., J.R.L., G.W.C.), Abbott Park, Illinois 60064"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Russell","family":"Turner","sequence":"additional","affiliation":[{"name":"Mayo Clinic (R.T.), Rochester, Minnesota 55905"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Curtis M.","family":"Tyree","sequence":"additional","affiliation":[{"name":"Ligand Pharmaceuticals, Inc. (C.M.T., J.H., M.E., J.R., J.N.M.), San Diego, California 92121"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junlian","family":"Hu","sequence":"additional","affiliation":[{"name":"Ligand Pharmaceuticals, Inc. (C.M.T., J.H., M.E., J.R., J.N.M.), San Diego, California 92121"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marc","family":"Elgort","sequence":"additional","affiliation":[{"name":"Ligand Pharmaceuticals, Inc. (C.M.T., J.H., M.E., J.R., J.N.M.), San Diego, California 92121"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jon","family":"Rosen","sequence":"additional","affiliation":[{"name":"Ligand Pharmaceuticals, Inc. (C.M.T., J.H., M.E., J.R., J.N.M.), San Diego, California 92121"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey N.","family":"Miner","sequence":"additional","affiliation":[{"name":"Ligand Pharmaceuticals, Inc. (C.M.T., J.H., M.E., J.R., J.N.M.), San Diego, California 92121"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"80","reference":[{"key":"2020071614261924700_R1","doi-asserted-by":"crossref","first-page":"704","DOI":"10.1136\/bjo.82.6.704","article-title":"Systemic corticosteroid therapy\u2014side effects and their management.","volume":"82","author":"Stanbury","year":"1998","journal-title":"Br J Ophthalmol"},{"key":"2020071614261924700_R2","doi-asserted-by":"crossref","first-page":"557","DOI":"10.1042\/cs0940557","article-title":"Anti-inflammatory actions of gluco-corticoids: molecular mechanisms [editorial].","volume":"94","author":"Barnes","year":"1998","journal-title":"Clin Sci (Colch)"},{"key":"2020071614261924700_R3","doi-asserted-by":"crossref","first-page":"841","DOI":"10.1016\/0092-8674(95)90200-7","article-title":"The RXR heterodimers and orphan receptors.","volume":"83","author":"Mangelsdorf","year":"1995","journal-title":"Cell"},{"key":"2020071614261924700_R4","doi-asserted-by":"crossref","first-page":"889","DOI":"10.1126\/science.3283939","article-title":"The steroid and thyroid hormone receptor superfamily.","volume":"240","author":"Evans","year":"1988","journal-title":"Science"},{"key":"2020071614261924700_R5","doi-asserted-by":"crossref","first-page":"423","DOI":"10.1016\/0968-0004(91)90168-U","article-title":"Regulatory crosstalk at composite response elements.","volume":"16","author":"Miner","year":"1991","journal-title":"Trends Biochem Sci"},{"key":"2020071614261924700_R6","doi-asserted-by":"crossref","first-page":"1266","DOI":"10.1126\/science.2119054","article-title":"Transcription factor interactions: selectors of positive or negative regulation from a single DNA element.","volume":"249","author":"Diamond","year":"1990","journal-title":"Science"},{"key":"2020071614261924700_R7","doi-asserted-by":"crossref","first-page":"1189","DOI":"10.1016\/0092-8674(90)90395-U","article-title":"Antitumor promotion and antiinflammation: down-modulation of AP-1 (Fos\/Jun) activity by glucocorticoid hormone.","volume":"62","author":"Jonat","year":"1990","journal-title":"Cell"},{"key":"2020071614261924700_R8","doi-asserted-by":"crossref","first-page":"152","DOI":"10.1016\/S1043-2760(97)00006-4","article-title":"Nuclear factor-\u03baB repression in anti-inflammation and immunosuppression by glucocorticoids.","volume":"8","author":"van der Burg","year":"1997","journal-title":"Trends Endocrinol Metab"},{"key":"2020071614261924700_R9","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/S0065-2776(08)60740-3","article-title":"NF-IL6 and NF-\u03baB in cytokine gene regulation.","volume":"65","author":"Akira","year":"1997","journal-title":"Adv Immunol"},{"key":"2020071614261924700_R10","first-page":"1","article-title":"Transcriptional repression as a molecular basis of the anti-inflammatory action of glucocorticoids.","author":"Heck","year":"1998"},{"key":"2020071614261924700_R11","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1016\/S0960-0760(97)00181-7","article-title":"Analysis of glucocorticoid signalling by gene targeting.","volume":"65","author":"Reichardt","year":"1998","journal-title":"J Steroid Biochem Mol Biol"},{"key":"2020071614261924700_R12","doi-asserted-by":"crossref","first-page":"1245","DOI":"10.1210\/mend.11.9.9979","article-title":"Synthetic glucocorticoids that dissociate transactivation and AP-1 transrepression exhibit antiinflammatory activity in vivo.","volume":"11","author":"Vayssiere","year":"1997","journal-title":"Mol Endocrinol"},{"key":"2020071614261924700_R13","doi-asserted-by":"crossref","first-page":"1975","DOI":"10.4049\/jimmunol.166.3.1975","article-title":"Therapeutic benefit of a dissociated glucocorticoid and the relevance of in vitro separation of transrepression from transactivation activity.","volume":"166","author":"Belvisi","year":"2001","journal-title":"J Immunol"},{"key":"2020071614261924700_R14","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1016\/S1043-2760(00)00357-X","article-title":"Novel glucocorticoid receptor coactivator effector mechanisms.","volume":"12","author":"Jenkins","year":"2001","journal-title":"Trends Endocrinol Metab"},{"key":"2020071614261924700_R15","doi-asserted-by":"crossref","first-page":"2314","DOI":"10.1101\/gad.827900","article-title":"The glucocorticoid receptor inhibits NF\u03baB by interfering with serine-2 phosphorylation of the RNA polymerase II carboxy-terminal domain.","volume":"14","author":"Nissen","year":"2000","journal-title":"Genes Dev"},{"key":"2020071614261924700_R16","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1038\/35093131","article-title":"CREB regulates hepatic gluconeogenesis through the coactivator PGC-1.","volume":"413","author":"Herzig","year":"2001","journal-title":"Nature"},{"key":"2020071614261924700_R17","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":"2020071614261924700_R18","doi-asserted-by":"crossref","first-page":"4948","DOI":"10.1073\/pnas.93.10.4948","article-title":"GRIP1, a novel mouse protein that serves as a transcriptional coactivator in yeast for the hormone binding domains of steroid receptors.","volume":"93","author":"Hong","year":"1996","journal-title":"Proc Natl Acad Sci USA"},{"key":"2020071614261924700_R19","doi-asserted-by":"crossref","first-page":"6071","DOI":"10.1093\/emboj\/20.21.6071","article-title":"Factor recruitment and TIF2\/GRIP1 corepressor activity at a collagenase-3 response element that mediates regulation by phorbol esters and hormones.","volume":"20","author":"Rogatsky","year":"2001","journal-title":"EMBO J"},{"key":"2020071614261924700_R20","doi-asserted-by":"crossref","first-page":"290","DOI":"10.1111\/j.1749-6632.2002.tb04229.x","article-title":"Stress hormones, proinflammatory and antiinflammatory cytokines, and autoimmunity.","volume":"966","author":"Elenkov","year":"2002","journal-title":"Ann NY Acad Sci"},{"key":"2020071614261924700_R21","doi-asserted-by":"crossref","first-page":"482","DOI":"10.1210\/mend.12.4.0090","article-title":"Further characterization of the glucocorticoid response unit in the phosphoenolpyruvate carboxykinase gene. The role of the glucocorticoid receptor-binding sites.","volume":"12","author":"Scott","year":"1998","journal-title":"Mol Endocrinol"},{"key":"2020071614261924700_R22","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1249\/00005768-199006000-00009","article-title":"Glucocorticoid-mediated induction of glutamine synthetase in skeletal muscle.","volume":"22","author":"Max","year":"1990","journal-title":"Med Sci Sports Exerc"},{"key":"2020071614261924700_R23","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1042\/bj2480397","article-title":"Activity of a gelsolin-like actin modulator in rat skeletal muscle under protein catabolic conditions.","volume":"248","author":"D\u2019Haese","year":"1987","journal-title":"Biochem J"},{"key":"2020071614261924700_R24","doi-asserted-by":"crossref","first-page":"919","DOI":"10.1089\/dna.1997.16.919","article-title":"Glucocorticoid-dependent transcriptional repression of the osteocalcin gene by competitive binding at the TATA box.","volume":"16","author":"Meyer","year":"1997","journal-title":"DNA Cell Biol"},{"key":"2020071614261924700_R25","doi-asserted-by":"crossref","first-page":"4382","DOI":"10.1210\/endo.140.10.7034","article-title":"Stimulation of osteoprotegerin ligand and inhibition of osteoprotegerin production by glucocorticoids in human osteoblastic lineage cells: potential paracrine mechanisms of glucocorticoid-induced osteoporosis.","volume":"140","author":"Hofbauer","year":"1999","journal-title":"Endocrinology"},{"key":"2020071614261924700_R26","doi-asserted-by":"crossref","first-page":"479","DOI":"10.1093\/ndt\/16.3.479","article-title":"Glucocorticoid decreases circulating osteoprotegerin (OPG): possible mechanism for glucocorticoid induced osteoporosis.","volume":"16","author":"Sasaki","year":"2001","journal-title":"Nephrol Dial Transplant"},{"key":"2020071614261924700_R27","doi-asserted-by":"crossref","first-page":"3365","DOI":"10.1016\/S0960-894X(98)00608-8","article-title":"5-Alkyl 1,2-dihydrochromeno[3,4-f]quinolines: a novel class of nonsteroidal progesterone receptor modulators.","volume":"8","author":"Zhi","year":"1998","journal-title":"Bioorg Med Chem Lett"},{"key":"2020071614261924700_R28","doi-asserted-by":"crossref","first-page":"4481","DOI":"10.1021\/jm010367u","article-title":"Nonsteroidal selective glucocorticoid modulators: the effect of C-5 alkyl substitution on the transcriptional activation\/repression profile of 2,5-dihydro-10-methoxy-2,2,4-trimethyl-1H-[1]benzopyrano[3,4-f]quinolines.","volume":"44","author":"Elmore","year":"2001","journal-title":"J Med Chem"},{"key":"2020071614261924700_R29","doi-asserted-by":"crossref","first-page":"154","DOI":"10.1002\/(SICI)1097-4644(19980501)69:2<154::AID-JCB6>3.0.CO;2-R","article-title":"Multiple levels of steroid hormone-dependent control of osteocalcin during osteoblast differentiation: glucocorticoid regulation of basal and vitamin D stimulated gene expression.","volume":"69","author":"Shalhoub","year":"1998","journal-title":"J Cell Biochem"},{"key":"2020071614261924700_R30","first-page":"1178","article-title":"Determinants of promoter-specific activity by glucocorticoid receptor.","volume":"10","author":"Guido","year":"1996","journal-title":"Mol Endocrinol"},{"key":"2020071614261924700_R31","doi-asserted-by":"crossref","first-page":"733","DOI":"10.1177\/014107687807101006","article-title":"Hormonal status in normal, osteoporotic and corticosteroid-treated postmenopausal women.","volume":"71","author":"Crilly","year":"1978","journal-title":"J R Soc Med"},{"key":"2020071614261924700_R32","first-page":"337","article-title":"Investigation of the carrageenin-induced rat paw edema assay and correlation between anti-inflammatory activity and gastric hemorrhage production in the rat.","volume":"185","author":"Walz","year":"1970","journal-title":"Arch Int Pharmacodyn Ther"},{"key":"2020071614261924700_R33","doi-asserted-by":"crossref","first-page":"2060","DOI":"10.1002\/1529-0131(199910)42:10<2060::AID-ANR6>3.0.CO;2-L","article-title":"A new spin on an old model: in vivo evaluation of disease progression by magnetic resonance imaging with respect to standard inflammatory parameters and histopathology in the adjuvant arthritic rat.","volume":"42","author":"Jacobson","year":"1999","journal-title":"Arthritis Rheum"},{"key":"2020071614261924700_R34","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1002\/art.1780030204","article-title":"The physiologic effects of dexamethasone.","volume":"3","author":"West","year":"1960","journal-title":"Arthritis Rheum"},{"key":"2020071614261924700_R35","doi-asserted-by":"crossref","first-page":"507","DOI":"10.1097\/00041552-200107000-00005","article-title":"Selective aspects of the insulin resistance syndrome.","volume":"10","author":"Corry","year":"2001","journal-title":"Curr Opin Nephrol Hypertens"},{"key":"2020071614261924700_R36","doi-asserted-by":"crossref","first-page":"557","DOI":"10.1002\/jbmr.5650040415","article-title":"Differential effects of gonadal function on bone histomorphometry in male and female rats.","volume":"4","author":"Turner","year":"1989","journal-title":"J Bone Miner Res"},{"key":"2020071614261924700_R37","first-page":"155","article-title":"A manual of methods for baculovirus vectors and insect cell culture procedures.","author":"Summers","year":"1987","journal-title":"Tex Agric Exp Stn"},{"key":"2020071614261924700_R38","doi-asserted-by":"crossref","first-page":"314","DOI":"10.1016\/0003-2697(79)90664-X","article-title":"An hydroxylapatite batch assay for the quantitation of 1\u03b1,25-dihydroxyvitamin D3-receptor complexes.","volume":"92","author":"Wecksler","year":"1979","journal-title":"Anal Biochem"},{"key":"2020071614261924700_R39","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1016\/0165-6147(89)90266-6","article-title":"Calculating receptor number from binding experiments using same compound as radioligand and competitor.","volume":"10","author":"DeBlasi","year":"1989","journal-title":"Trends Pharmacol Sci"},{"key":"2020071614261924700_R40","doi-asserted-by":"crossref","first-page":"456","DOI":"10.1016\/0042-6822(73)90341-3","article-title":"A new technique for the assay of infectivity of human adenovirus 5 DNA.","volume":"52","author":"Graham","year":"1973","journal-title":"Virology"},{"key":"2020071614261924700_R41","doi-asserted-by":"crossref","first-page":"703","DOI":"10.1016\/0092-8674(92)90234-4","article-title":"The mechanism of RU486 antagonism is dependent on the conformation of the carboxy-terminal tail of the human progesterone receptor.","volume":"69","author":"Vegeto","year":"1992","journal-title":"Cell"},{"key":"2020071614261924700_R42","doi-asserted-by":"crossref","first-page":"360","DOI":"10.1016\/S1043-2760(01)00457-X","article-title":"PGC-1, a versatile coactivator.","volume":"12","author":"Knutti","year":"2001","journal-title":"Trends Endocrinol Metab"},{"key":"2020071614261924700_R43","doi-asserted-by":"crossref","first-page":"798","DOI":"10.1038\/372798a0","article-title":"Activation of stress-activated protein kinase by MEKK1 phosphorylation of its activator SEK1.","volume":"372","author":"Yan","year":"1994","journal-title":"Nature"},{"key":"2020071614261924700_R44","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1016\/0092-8674(87)90753-7","article-title":"Colocalization of DNA-binding and transcriptional activation functions in the human glucocorticoid receptor.","volume":"49","author":"Hollenberg","year":"1987","journal-title":"Cell"}],"container-title":["Molecular Endocrinology"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/academic.oup.com\/mend\/article-pdf\/17\/5\/860\/8964507\/mend0860.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/academic.oup.com\/mend\/article-pdf\/17\/5\/860\/8964507\/mend0860.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2020,7,17]],"date-time":"2020-07-17T02:18:11Z","timestamp":1594952291000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/mend\/article\/17\/5\/860\/2747410"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2003,5,1]]},"references-count":44,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2003,5,1]]}},"URL":"https:\/\/doi.org\/10.1210\/me.2002-0355","relation":{},"ISSN":["0888-8809","1944-9917"],"issn-type":[{"value":"0888-8809","type":"print"},{"value":"1944-9917","type":"electronic"}],"subject":[],"published":{"date-parts":[[2003,5,1]]}}}