title: Potent cholesteryl ester transfer protein inhibitors of reduced lipophilicity: 1,1'-spiro-substituted hexahydrofuroquinoline derivatives.
abstract: A series of 1,1'-spiro-substituted hexahydrofuroquinoline derivatives exhibiting potent cholesteryl ester transfer protein (CETP) inhibition at reduced lipophilicity was identified. A focused structure-activity relationship (SAR) exploration led to the potent and comparatively polar CETP inhibitor 26 showing robust high density lipoprotein-cholesterol (HDL-C) elevation and low density lipoprotein-cholesterol (LDL-C) reduction in transgenic hCETP/hApoB-100 mice. Compound 26 was also shown to positively differentiate from highly lipophilic CETP inhibitors in its complete elimination from fat tissue in hCETP transgenic mice as evident within 21 days after cessation of treatment. In addition, compound 26 showed no significant effects on aldosterone secretion from H295R cells, as well as no significant effects on blood pressure and electrocardiogram parameters in telemetrized cynomolgus monkeys.
authors.affiliation: Departments of Medicinal Chemistry, §Cardiometabolic Diseases, ⊥Drug Discovery Support, and ∥Lead Identification, Boehringer Ingelheim Pharma GmbH & Co. KG , Birkendorfer Strasse 65, 88397 Biberach an der Riss, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Trieselmann
authors.forename: Holger
authors.initials: H
authors.lastname: Wagner
authors.forename: Klaus
authors.initials: K
authors.lastname: Fuchs
authors.forename: Dieter
authors.initials: D
authors.lastname: Hamprecht
authors.forename: Daniela
authors.initials: D
authors.lastname: Berta
authors.forename: Paolo
authors.initials: P
authors.lastname: Cremonesi
authors.forename: Rüdiger
authors.initials: R
authors.lastname: Streicher
authors.forename: Gerd
authors.initials: G
authors.lastname: Luippold
authors.forename: Astrid
authors.initials: A
authors.lastname: Volz
authors.forename: Michael
authors.initials: M
authors.lastname: Markert
authors.forename: Herbert
authors.initials: H
authors.lastname: Nar
mesh_terms: D000818:Animals; D000924:Anticholesteremic Agents / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D053480:Cholesterol Ester Transfer Proteins / Q000037:antagonists & inhibitors*; D008076:Cholesterol, HDL / Q000097:blood; D006801:Humans; D006912:Hydroxyquinolines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D008252:Macaca fascicularis; D008822:Mice, Transgenic; D011804:Quinolines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D013141:Spiro Compounds / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: C000595642:4-isopropyl-7,7-dimethyl-3-(4-(trifluoromethyl)phenyl)-2',3',5',6,6',7,8,9-octahydro-3H-spiro(furo(3,4-c)quinoline-1,4'-pyran)-9-ol; D000924:Anticholesteremic Agents; C506642:CETP protein, human; D053480:Cholesterol Ester Transfer Proteins; D008076:Cholesterol, HDL; D006912:Hydroxyquinolines; D011804:Quinolines; D013141:Spiro Compounds