title: 4-Bicyclic heteroaryl-piperidine derivatives as potent, orally bioavailable stearoyl-CoA desaturase-1 (SCD1) inhibitors: part 2. Pyridazine-based analogs.
abstract: Design, synthesis, and biological evaluation of pyridazine-based, 4-bicyclic heteroaryl-piperidine derivatives as potent stearoyl-CoA desaturase-1 (SCD1) inhibitors are described. In a chronic study of selected analog (3e) in Zucker fa/fa (ZF) rat, dose-dependent decrease of body weight gain and plasma fatty acid desaturation index (DI) in both C16 and C18 are also demonstrated. The results indicate that the plasma fatty acid DI may serve as an indicator for direct target engagement and biomarker for SCD1 inhibition.
authors.affiliation: Cardiovascular and Metabolism Research, Janssen Research and Development, LLC, Welsh & McKean Roads, Spring House, PA 19477, USA. Electronic address: shyhyang99@yahoo.com.
authors.forename: Shyh-Ming
authors.initials: SM
authors.lastname: Yang
authors.affiliation: Cardiovascular and Metabolism Research, Janssen Research and Development, LLC, Welsh & McKean Roads, Spring House, PA 19477, USA.
authors.forename: Yuting
authors.initials: Y
authors.lastname: Tang
authors.affiliation: Cardiovascular and Metabolism Research, Janssen Research and Development, LLC, Welsh & McKean Roads, Spring House, PA 19477, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Rano
authors.affiliation: Cardiovascular and Metabolism Research, Janssen Research and Development, LLC, Welsh & McKean Roads, Spring House, PA 19477, USA.
authors.forename: Huajun
authors.initials: H
authors.lastname: Lu
authors.affiliation: Cardiovascular and Metabolism Research, Janssen Research and Development, LLC, Welsh & McKean Roads, Spring House, PA 19477, USA.
authors.forename: Gee-Hong
authors.initials: GH
authors.lastname: Kuo
authors.affiliation: Cardiovascular and Metabolism Research, Janssen Research and Development, LLC, Welsh & McKean Roads, Spring House, PA 19477, USA.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Gaul
authors.affiliation: Cardiovascular and Metabolism Research, Janssen Research and Development, LLC, Welsh & McKean Roads, Spring House, PA 19477, USA.
authors.forename: Yaxin
authors.initials: Y
authors.lastname: Li
authors.affiliation: Cardiovascular and Metabolism Research, Janssen Research and Development, LLC, Welsh & McKean Roads, Spring House, PA 19477, USA.
authors.forename: George
authors.initials: G
authors.lastname: Ho
authors.affiliation: Cardiovascular and Metabolism Research, Janssen Research and Development, LLC, Welsh & McKean Roads, Spring House, PA 19477, USA.
authors.forename: Wensheng
authors.initials: W
authors.lastname: Lang
authors.affiliation: Cardiovascular and Metabolism Research, Janssen Research and Development, LLC, Welsh & McKean Roads, Spring House, PA 19477, USA.
authors.forename: James G
authors.initials: JG
authors.lastname: Conway
authors.affiliation: Cardiovascular and Metabolism Research, Janssen Research and Development, LLC, Welsh & McKean Roads, Spring House, PA 19477, USA.
authors.forename: Yin
authors.initials: Y
authors.lastname: Liang
authors.affiliation: Cardiovascular and Metabolism Research, Janssen Research and Development, LLC, Welsh & McKean Roads, Spring House, PA 19477, USA.
authors.forename: James M
authors.initials: JM
authors.lastname: Lenhard
authors.affiliation: Cardiovascular and Metabolism Research, Janssen Research and Development, LLC, Welsh & McKean Roads, Spring House, PA 19477, USA.
authors.forename: Keith T
authors.initials: KT
authors.lastname: Demarest
authors.affiliation: Cardiovascular and Metabolism Research, Janssen Research and Development, LLC, Welsh & McKean Roads, Spring House, PA 19477, USA.
authors.forename: William V
authors.initials: WV
authors.lastname: Murray
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D001643:Bridged Bicyclo Compounds / Q000737:chemistry*; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D006207:Half-Life; D006801:Humans; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D009765:Obesity / Q000188:drug therapy; D011724:Pyridazines / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D011924:Rats, Zucker; D013230:Stearoyl-CoA Desaturase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D001643:Bridged Bicyclo Compounds; D004791:Enzyme Inhibitors; D011724:Pyridazines; C062482:pyridazine; D013230:Stearoyl-CoA Desaturase
keywords: Desaturation index; SCD1 inhibitors; Stearoyl-CoA desaturase; obesity