title: Discovery and characterization of aminopiperidinecoumarin melanin concentrating hormone receptor 1 antagonists.
abstract: 4-(1-Benzo[1,3]dioxol-5-ylmethylpiperidine-4-ylmethyl)-6-chlorochromen-2-one (7) is a potent, orally bioavailable melanin concentrating hormone receptor 1 (MCHr1) antagonist that causes dose-dependent weight loss in diet-induced obese mice. Further evaluation of 7 in an anesthetized dog model of cardiovascular safety revealed adverse hemodynamic effects at a plasma concentration comparable to the minimally effective therapeutic concentration. These results highlight the need for scrutiny of the cardiovascular safety profile of MCHr1 antagonists.
authors.affiliation: Metabolic Disease Research, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, Illinois 60064, USA. phil.r.kym@abbott.com
authors.forename: Philip R
authors.initials: PR
authors.lastname: Kym
authors.forename: Rajesh
authors.initials: R
authors.lastname: Iyengar
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Souers
authors.forename: John K
authors.initials: JK
authors.lastname: Lynch
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Judd
authors.forename: Ju
authors.initials: J
authors.lastname: Gao
authors.forename: Jennifer
authors.initials: J
authors.lastname: Freeman
authors.forename: Mathew
authors.initials: M
authors.lastname: Mulhern
authors.forename: Gang
authors.initials: G
authors.lastname: Zhao
authors.forename: Anil
authors.initials: A
authors.lastname: Vasudevan
authors.forename: Dariusz
authors.initials: D
authors.lastname: Wodka
authors.forename: Christopher
authors.initials: C
authors.lastname: Blackburn
authors.forename: Jim
authors.initials: J
authors.lastname: Brown
authors.forename: Jennifer Lee
authors.initials: JL
authors.lastname: Che
authors.forename: Courtney
authors.initials: C
authors.lastname: Cullis
authors.forename: Su Jen
authors.initials: SJ
authors.lastname: Lai
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: LaMarche
authors.forename: Tom
authors.initials: T
authors.lastname: Marsilje
authors.forename: Jon
authors.initials: J
authors.lastname: Roses
authors.forename: Todd
authors.initials: T
authors.lastname: Sells
authors.forename: Brad
authors.initials: B
authors.lastname: Geddes
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Govek
authors.forename: Michael
authors.initials: M
authors.lastname: Patane
authors.forename: Dennis
authors.initials: D
authors.lastname: Fry
authors.forename: Brian D
authors.initials: BD
authors.lastname: Dayton
authors.forename: Sevan
authors.initials: S
authors.lastname: Brodjian
authors.forename: Doug
authors.initials: D
authors.lastname: Falls
authors.forename: Michael
authors.initials: M
authors.lastname: Brune
authors.forename: Eugene
authors.initials: E
authors.lastname: Bush
authors.forename: Robin
authors.initials: R
authors.lastname: Shapiro
authors.forename: Victoria
authors.initials: V
authors.lastname: Knourek-Segel
authors.forename: Thomas
authors.initials: T
authors.lastname: Fey
authors.forename: Cathleen
authors.initials: C
authors.lastname: McDowell
authors.forename: Glenn A
authors.initials: GA
authors.lastname: Reinhart
authors.forename: Lee C
authors.initials: LC
authors.lastname: Preusser
authors.forename: Kennan
authors.initials: K
authors.lastname: Marsh
authors.forename: Lisa
authors.initials: L
authors.lastname: Hernandez
authors.forename: Hing L
authors.initials: HL
authors.lastname: Sham
authors.forename: Christine A
authors.initials: CA
authors.lastname: Collins
mesh_terms: D000284:Administration, Oral; D000818:Animals; D019440:Anti-Obesity Agents / Q000009:adverse effects / Q000138:chemical synthesis / Q000494:pharmacology; D001682:Biological Availability; D001794:Blood Pressure / Q000187:drug effects; D001921:Brain / Q000378:metabolism; D045744:Cell Line, Tumor; D003374:Coumarins / Q000009:adverse effects / Q000138:chemical synthesis* / Q000494:pharmacology; D004285:Dogs; D004435:Eating / Q000187:drug effects; D004734:Energy Metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008820:Mice, Obese; D009200:Myocardial Contraction / Q000187:drug effects; D010880:Piperidines / Q000009:adverse effects / Q000138:chemical synthesis* / Q000494:pharmacology; D011869:Radioligand Assay; D011979:Receptors, Pituitary Hormone / Q000037:antagonists & inhibitors*; D017481:Receptors, Somatostatin / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
chemical_list: D019440:Anti-Obesity Agents; D003374:Coumarins; C491209:Mchr1 protein, mouse; D010880:Piperidines; D011979:Receptors, Pituitary Hormone; D017481:Receptors, Somatostatin; C092274:melanin-concentrating hormone receptor