title: Constrained 7-fluorocarboxychromone-4-aminopiperidine based Melanin-concentrating hormone receptor 1 antagonists: the effects of chirality on substituted indan-1-ylamines.
abstract: The incorporation of constrained tertiary amines into an existing class of N-benzyl-4-aminopiperidinyl chromone-based MCHr1 antagonists led to the identification of a series of chiral racemic compounds that displayed good to excellent functional potency, binding affinity, and selectivity over the hERG channel. Further separation of two distinct chiral racemic compounds into their corresponding pairs of enantiomers revealed a considerable selectivity for MCHr1 for one configuration, in addition to a striking difference in oral exposure between one pair of enantiomers in diet-induced obese mice. Oral administration of the most potent compound in this class in the same animal model led to significant reduction of fat mass in a semi-chronic model for weight loss.
authors.affiliation: Metabolic Disease Research, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, IL 60064, USA. andrew.souers@abbott.com
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Souers
authors.forename: Rajesh R
authors.initials: RR
authors.lastname: Iyengar
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Judd
authors.forename: David W A
authors.initials: DW
authors.lastname: Beno
authors.forename: Ju
authors.initials: J
authors.lastname: Gao
authors.forename: Gang
authors.initials: G
authors.lastname: Zhao
authors.forename: Michael E
authors.initials: ME
authors.lastname: Brune
authors.forename: James J
authors.initials: JJ
authors.lastname: Napier
authors.forename: Mathew M
authors.initials: MM
authors.lastname: Mulhern
authors.forename: John K
authors.initials: JK
authors.lastname: Lynch
authors.forename: Jennifer C
authors.initials: JC
authors.lastname: Freeman
authors.forename: Dariusz
authors.initials: D
authors.lastname: Wodka
authors.forename: Chong J
authors.initials: CJ
authors.lastname: Chen
authors.forename: H Doug
authors.initials: HD
authors.lastname: Falls
authors.forename: Sevan
authors.initials: S
authors.lastname: Brodjian
authors.forename: Brian D
authors.initials: BD
authors.lastname: Dayton
authors.forename: Gilbert J
authors.initials: GJ
authors.lastname: Diaz
authors.forename: Eugene N
authors.initials: EN
authors.lastname: Bush
authors.forename: Robin
authors.initials: R
authors.lastname: Shapiro
authors.forename: Brian A
authors.initials: BA
authors.lastname: Droz
authors.forename: Victoria
authors.initials: V
authors.lastname: Knourek-Segel
authors.forename: Lisa E
authors.initials: LE
authors.lastname: Hernandez
authors.forename: Kennan C
authors.initials: KC
authors.lastname: Marsh
authors.forename: Regina M
authors.initials: RM
authors.lastname: Reilly
authors.forename: Hing L
authors.initials: HL
authors.lastname: Sham
authors.forename: Christine A
authors.initials: CA
authors.lastname: Collins
authors.forename: Philip R
authors.initials: PR
authors.lastname: Kym
mesh_terms: D000818:Animals; D019440:Anti-Obesity Agents / Q000138:chemical synthesis / Q000494:pharmacology; D001067:Appetite Depressants / Q000494:pharmacology; D001835:Body Weight / Q000187:drug effects; D001921:Brain / Q000378:metabolism; D002460:Cell Line; D002867:Chromones / Q000138:chemical synthesis* / Q000494:pharmacology*; D004032:Diet; D004041:Dietary Fats; D051638:Ether-A-Go-Go Potassium Channels / Q000187:drug effects; D005277:Fenfluramine / Q000494:pharmacology; D007202:Indicators and Reagents; D051379:Mice; D008968:Molecular Conformation; D010880:Piperidines / Q000138:chemical synthesis* / Q000494:pharmacology*; D026902:Potassium Channel Blockers / Q000138:chemical synthesis / Q000494:pharmacology; D017481:Receptors, Somatostatin / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
chemical_list: C518721:7-fluorocarboxychromone-4-aminopiperidine; D019440:Anti-Obesity Agents; D001067:Appetite Depressants; D002867:Chromones; D004041:Dietary Fats; D051638:Ether-A-Go-Go Potassium Channels; D007202:Indicators and Reagents; C491209:Mchr1 protein, mouse; D010880:Piperidines; D026902:Potassium Channel Blockers; D017481:Receptors, Somatostatin; D005277:Fenfluramine