{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,12]],"date-time":"2025-10-12T19:57:14Z","timestamp":1760299034774,"version":"build-2065373602"},"reference-count":14,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2014,11,12]],"date-time":"2014-11-12T00:00:00Z","timestamp":1415750400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["chemistry-europe.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["ChemMedChem"],"published-print":{"date-parts":[[2015,2]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Ergolines were recently identified as a novel class of H3 receptor (H3R) inverse agonists. Although their optimization led to drug candidates with encouraging properties for the treatment of narcolepsy, brain penetration remained low. To overcome this issue, ergoline <jats:bold>1<\/jats:bold> ((6a<jats:italic>R<\/jats:italic>,9<jats:italic>R<\/jats:italic>,10a<jats:italic>R<\/jats:italic>)\u20104\u2010(2\u2010(dimethylamino)ethyl)\u2010<jats:italic>N<\/jats:italic>\u2010phenyl\u20109\u2010(pyrrolidine\u20101\u2010carbonyl)\u20106,6a,8,9,10,10a\u2010hexahydroindolo[4,3\u2010<jats:italic>fg<\/jats:italic>]quinoline\u20107(4<jats:italic>H<\/jats:italic>)\u2010carboxamide)) was transformed into a series of indole derivatives with high H3R affinity. These new molecules were profiled by simultaneous determination of their brain receptor occupancy (RO) levels and pharmacodynamic (PD) effects in mice. These efforts culminated in the discovery of <jats:bold>15\u2009m<\/jats:bold> ((<jats:italic>R<\/jats:italic>)\u20101\u2010isopropyl\u20105\u2010(1\u2010(2\u2010(2\u2010methylpyrrolidin\u20101\u2010yl)ethyl)\u20101<jats:italic>H<\/jats:italic>\u2010indol\u20104\u2010yl)pyridin\u20102(1<jats:italic>H<\/jats:italic>)\u2010one), which has an ideal profile showing a strong correlation of PD effects with RO, and no measurable safety liabilities. Its desirably short duration of action was confirmed by electroencephalography (EEG) measurements in rats.<\/jats:p>","DOI":"10.1002\/cmdc.201402418","type":"journal-article","created":{"date-parts":[[2014,11,12]],"date-time":"2014-11-12T10:35:02Z","timestamp":1415788502000},"page":"266-275","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["From Ergolines to Indoles: Improved Inhibitors of the Human H3 Receptor for the Treatment of Narcolepsy"],"prefix":"10.1002","volume":"10","author":[{"given":"Yves P.","family":"Auberson","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thomas","family":"Troxler","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xuechun","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Charles R.","family":"Yang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dominik","family":"Feuerbach","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yu\u2010Chih","family":"Liu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bharat","family":"Lagu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mark","family":"Perrone","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lijun","family":"Lei","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaoxia","family":"Shen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dushan","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chunxiu","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tie\u2010Lin","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Karin","family":"Briner","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mark G.","family":"Bock","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2014,11,12]]},"reference":[{"doi-asserted-by":"publisher","key":"e_1_2_6_1_2","DOI":"10.1124\/jpet.110.170134"},{"doi-asserted-by":"publisher","key":"e_1_2_6_2_2","DOI":"10.2174\/156802608784936728"},{"doi-asserted-by":"publisher","key":"e_1_2_6_3_2","DOI":"10.1002\/cmdc.201402055"},{"doi-asserted-by":"publisher","key":"e_1_2_6_4_2","DOI":"10.1124\/jpet.107.135343"},{"doi-asserted-by":"publisher","key":"e_1_2_6_5_2","DOI":"10.1124\/jpet.112.194126"},{"doi-asserted-by":"publisher","key":"e_1_2_6_6_2","DOI":"10.1124\/jpet.112.199794"},{"key":"e_1_2_6_7_2","first-page":"15","volume":"33","author":"Cho S.\u2010D.","year":"1996","journal-title":"J. Heterocycl. Chem."},{"unstructured":"Compound15\u2009bdemonstrated rapid and extensive brain penetration (1250\u2005ng\u2009g\u22121 30\u2005min after an oral dose at 10\u2005mg\u2009kg\u22121; brain\/plasma concentration ratio: 4.9) followed by rapid elimination (275\u2005mg\u2009g\u22121remaining in the brain after 4\u2005h).","key":"e_1_2_6_8_2"},{"unstructured":"Compound15\u2009mhas a water solubility of 0.106\u2005mMat pH\u20056.8. Permeability in MDR1\u2010MDCK cells:Papp=27.6\u00d710\u22126\u2005cm\u2009s\u22121 efflux ratio: 0.95.","key":"e_1_2_6_9_2"},{"doi-asserted-by":"publisher","key":"e_1_2_6_10_2","DOI":"10.1016\/0024-3205(84)90107-3"},{"unstructured":"For a description of the EEG method see:","key":"e_1_2_6_11_2"},{"doi-asserted-by":"publisher","key":"e_1_2_6_12_2","DOI":"10.1038\/npp.2012.244"},{"doi-asserted-by":"publisher","key":"e_1_2_6_13_2","DOI":"10.1073\/pnas.0600451103"},{"doi-asserted-by":"publisher","key":"e_1_2_6_14_2","DOI":"10.1007\/s13311-012-0150-9"}],"container-title":["ChemMedChem"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fcmdc.201402418","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/chemistry-europe.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cmdc.201402418","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,12]],"date-time":"2025-10-12T11:59:34Z","timestamp":1760270374000},"score":1,"resource":{"primary":{"URL":"https:\/\/chemistry-europe.onlinelibrary.wiley.com\/doi\/10.1002\/cmdc.201402418"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2014,11,12]]},"references-count":14,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2015,2]]}},"alternative-id":["10.1002\/cmdc.201402418"],"URL":"https:\/\/doi.org\/10.1002\/cmdc.201402418","archive":["Portico"],"relation":{},"ISSN":["1860-7179","1860-7187"],"issn-type":[{"type":"print","value":"1860-7179"},{"type":"electronic","value":"1860-7187"}],"subject":[],"published":{"date-parts":[[2014,11,12]]},"assertion":[{"value":"2014-09-26","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2014-11-12","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}